{"id":6553,"date":"2023-03-10T11:48:34","date_gmt":"2023-03-10T16:48:34","guid":{"rendered":"https:\/\/dalriadatx.com\/?post_type=articles&#038;p=6553"},"modified":"2024-02-19T16:45:15","modified_gmt":"2024-02-19T21:45:15","slug":"small-molecule-highlights-09-march-2023","status":"publish","type":"articles","link":"https:\/\/dalriadatx.com\/articles\/small-molecule-highlights-09-march-2023\/","title":{"rendered":"Small Molecule Highlights #09 \u2013 March 2023"},"content":{"rendered":"\t\t<div data-elementor-type=\"wp-post\" data-elementor-id=\"6553\" class=\"elementor elementor-6553\" data-elementor-post-type=\"articles\">\n\t\t\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-2468c2c elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"2468c2c\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-4e137d8 jltma-glass-effect-no\" data-id=\"4e137d8\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-882929c jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"882929c\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t<style>\/*! elementor - v3.20.0 - 26-03-2024 *\/\n.elementor-widget-text-editor.elementor-drop-cap-view-stacked .elementor-drop-cap{background-color:#69727d;color:#fff}.elementor-widget-text-editor.elementor-drop-cap-view-framed .elementor-drop-cap{color:#69727d;border:3px solid;background-color:transparent}.elementor-widget-text-editor:not(.elementor-drop-cap-view-default) .elementor-drop-cap{margin-top:8px}.elementor-widget-text-editor:not(.elementor-drop-cap-view-default) .elementor-drop-cap-letter{width:1em;height:1em}.elementor-widget-text-editor .elementor-drop-cap{float:left;text-align:center;line-height:1;font-size:50px}.elementor-widget-text-editor .elementor-drop-cap-letter{display:inline-block}<\/style>\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-2468c2c elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"2468c2c\" data-element_type=\"section\"><div class=\"elementor-container elementor-column-gap-default\"><div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-4e137d8 jltma-glass-effect-no\" data-id=\"4e137d8\" data-element_type=\"column\"><div class=\"elementor-widget-wrap elementor-element-populated\"><div class=\"elementor-element elementor-element-882929c jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"882929c\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\"><div class=\"elementor-widget-container\"><p>This issue highlights 8 small molecules reported in recent medicinal chemistry literature, out of the Journal of Medicinal Chemistry, ACS Medicinal Chemistry Letters, and the European Journal of Medicinal Chemistry. Interestingly, several unique scaffolds are represented by this list of compounds, including indazoles, pyrimidines, chromanes, and urea pyrazoles. These small molecules also present several MOAs including standard inhibition, agonism, antagonism and covalency. Enjoy!<\/p><\/div><\/div><\/div><\/div><\/div><\/section>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-d3e7f11 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"d3e7f11\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-4140dc5 jltma-glass-effect-no\" data-id=\"4140dc5\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-cc4a065 jltma-glass-effect-no elementor-widget elementor-widget-image\" data-id=\"cc4a065\" data-element_type=\"widget\" data-widget_type=\"image.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t<style>\/*! elementor - v3.20.0 - 26-03-2024 *\/\n.elementor-widget-image{text-align:center}.elementor-widget-image a{display:inline-block}.elementor-widget-image a img[src$=\".svg\"]{width:48px}.elementor-widget-image img{vertical-align:middle;display:inline-block}<\/style>\t\t\t\t\t\t\t<figure class=\"wp-caption\">\n\t\t\t\t\t\t\t\t\t\t<img fetchpriority=\"high\" decoding=\"async\" width=\"768\" height=\"587\" src=\"https:\/\/dalriadatx.com\/wp-content\/uploads\/Small-Molecule-Highlights-09-one-pager-768x587.jpg\" class=\"attachment-medium_large size-medium_large wp-image-6552\" alt=\"\" srcset=\"https:\/\/dalriadatx.com\/wp-content\/uploads\/Small-Molecule-Highlights-09-one-pager-768x587.jpg 768w, https:\/\/dalriadatx.com\/wp-content\/uploads\/Small-Molecule-Highlights-09-one-pager-300x229.jpg 300w, https:\/\/dalriadatx.com\/wp-content\/uploads\/Small-Molecule-Highlights-09-one-pager-1024x783.jpg 1024w, https:\/\/dalriadatx.com\/wp-content\/uploads\/Small-Molecule-Highlights-09-one-pager-1536x1175.jpg 1536w, https:\/\/dalriadatx.com\/wp-content\/uploads\/Small-Molecule-Highlights-09-one-pager-431x330.jpg 431w, https:\/\/dalriadatx.com\/wp-content\/uploads\/Small-Molecule-Highlights-09-one-pager-235x180.jpg 235w, https:\/\/dalriadatx.com\/wp-content\/uploads\/Small-Molecule-Highlights-09-one-pager.jpg 1718w\" sizes=\"(max-width: 768px) 100vw, 768px\" \/>\t\t\t\t\t\t\t\t\t\t\t<figcaption class=\"widget-image-caption wp-caption-text\">Small Molecule Highlights #09 \u2013 March 2023<\/figcaption>\n\t\t\t\t\t\t\t\t\t\t<\/figure>\n\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<div class=\"elementor-element elementor-element-e2c4e9e elementor-align-center jltma-glass-effect-no elementor-widget elementor-widget-button\" data-id=\"e2c4e9e\" data-element_type=\"widget\" data-widget_type=\"button.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t<div class=\"elementor-button-wrapper\">\n\t\t\t<a class=\"elementor-button elementor-button-link elementor-size-sm\" href=\"\/wp-content\/uploads\/Small-Molecule-Highlights-09-one-pager-with-summary.pdf\">\n\t\t\t\t\t\t<span class=\"elementor-button-content-wrapper\">\n\t\t\t\t\t\t<span class=\"elementor-button-text\">Download Summary<\/span>\n\t\t<\/span>\n\t\t\t\t\t<\/a>\n\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-530f9b5 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"530f9b5\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-e1435c1 jltma-glass-effect-no\" data-id=\"e1435c1\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-4b59dbf jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"4b59dbf\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-530f9b5 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"530f9b5\" data-element_type=\"section\"><div class=\"elementor-container elementor-column-gap-default\"><div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-e1435c1 jltma-glass-effect-no\" data-id=\"e1435c1\" data-element_type=\"column\"><div class=\"elementor-widget-wrap elementor-element-populated\"><div class=\"elementor-element elementor-element-4b59dbf jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"4b59dbf\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\"><div class=\"elementor-widget-container\"><h2><strong>Compound 14<\/strong><\/h2><\/div><\/div><\/div><\/div><\/div><\/section>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-fc3ef58 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"fc3ef58\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-e024f63 jltma-glass-effect-no\" data-id=\"e024f63\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-cbfaf9d jltma-glass-effect-no elementor-widget elementor-widget-image\" data-id=\"cbfaf9d\" data-element_type=\"widget\" data-widget_type=\"image.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t\t\t\t<figure class=\"wp-caption\">\n\t\t\t\t\t\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/dalriadatx.com\/wp-content\/uploads\/elementor\/thumbs\/Compound-14-1-q3bgcvqt24wvrvpwyx371b5j53wdeg7yghb4f71sgk.jpg\" title=\"Compound 14\" alt=\"Compound 14\" loading=\"lazy\" \/>\t\t\t\t\t\t\t\t\t\t\t<figcaption class=\"widget-image-caption wp-caption-text\">Compound 14<\/figcaption>\n\t\t\t\t\t\t\t\t\t\t<\/figure>\n\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-691f658 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"691f658\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-ff9c429 jltma-glass-effect-no\" data-id=\"ff9c429\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-fcb040d jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"fcb040d\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-691f658 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"691f658\" data-element_type=\"section\"><div class=\"elementor-container elementor-column-gap-default\"><div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-ff9c429 jltma-glass-effect-no\" data-id=\"ff9c429\" data-element_type=\"column\"><div class=\"elementor-widget-wrap elementor-element-populated\"><div class=\"elementor-element elementor-element-fcb040d jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"fcb040d\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\"><div class=\"elementor-widget-container\"><p><strong>Compound 14: <\/strong>This 2H\u2011Indazole-3-carboxamide has been reported <em>in J.Med.Chem.<\/em> as an EP4 antagonist as an anticancer immunotherapy with medicinal utility against colorectal cancer (CRC). EP4 is a G\u03b1<sub>s<\/sub>-coupled GPCR, with roles in cAMP pathways and PGE<sub>2<\/sub> immunosuppressive responses. In a cAMP assay, a hEP<sub>4<\/sub> IC<sub>50<\/sub> value of 1.1 nM was reported, whilst against EP1, EP2, and EP3, an IC<sub>50<\/sub> &gt; 10 \u00b5M was found. Across various hEP<sub>4<\/sub> assays (Ca<sup>2+<\/sup> flux, \u03b2-arrestin, and CRE), an IC<sub>50<\/sub> value of 2.1 nM, 0.9 nM, and 4.1 nM was observed. Against HLM, a T<sub>1\/2<\/sub> of 145 mins was found, with limited CYP inhibition (IC<sub>50<\/sub> &gt; 50 \u00b5M). At 5 mg\/kg (p.o.), an oral bioavailability (<em>F<\/em> %) of 46.8% was found. <em>In vivo<\/em> efficacy was also seen in a CT26 syngeneic tumor mouse model (at 100 mg\/kg, p.o.), with a TGI of 76%<\/p><p><strong>Reference: <\/strong><a href=\"https:\/\/doi.org\/10.1021\/acs.jmedchem.2c02058\" target=\"_blank\" rel=\"noopener\"><strong>https:\/\/doi.org\/10.1021\/acs.jmedchem.2c02058<\/strong><\/a><\/p><\/div><\/div><\/div><\/div><\/div><\/section>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-4dee8b7 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"4dee8b7\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-336a628 jltma-glass-effect-no\" data-id=\"336a628\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-b31fab9 jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"b31fab9\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-4dee8b7 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"4dee8b7\" data-element_type=\"section\"><div class=\"elementor-container elementor-column-gap-default\"><div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-336a628 jltma-glass-effect-no\" data-id=\"336a628\" data-element_type=\"column\"><div class=\"elementor-widget-wrap elementor-element-populated\"><div class=\"elementor-element elementor-element-b31fab9 jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"b31fab9\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\"><div class=\"elementor-widget-container\"><h2><strong>Compound 24<\/strong><\/h2><\/div><\/div><\/div><\/div><\/div><\/section>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-e4fa9f4 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"e4fa9f4\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-5bf3641 jltma-glass-effect-no\" data-id=\"5bf3641\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-6f335da jltma-glass-effect-no elementor-widget elementor-widget-image\" data-id=\"6f335da\" data-element_type=\"widget\" data-widget_type=\"image.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t\t\t\t<figure class=\"wp-caption\">\n\t\t\t\t\t\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/dalriadatx.com\/wp-content\/uploads\/elementor\/thumbs\/Compound-24-1-q3bgcwon8yy63hojtfhtlswzqhrqm5boslylwh0eac.jpg\" title=\"Compound 24\" alt=\"Compound 24\" loading=\"lazy\" \/>\t\t\t\t\t\t\t\t\t\t\t<figcaption class=\"widget-image-caption wp-caption-text\">Compound 24<\/figcaption>\n\t\t\t\t\t\t\t\t\t\t<\/figure>\n\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-3bc7a82 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"3bc7a82\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-2194942 jltma-glass-effect-no\" data-id=\"2194942\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-fd9c1bc jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"fd9c1bc\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-691f658 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"691f658\" data-element_type=\"section\"><div class=\"elementor-container elementor-column-gap-default\"><div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-ff9c429 jltma-glass-effect-no\" data-id=\"ff9c429\" data-element_type=\"column\"><div class=\"elementor-widget-wrap elementor-element-populated\"><div class=\"elementor-element elementor-element-fcb040d jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"fcb040d\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\"><div class=\"elementor-widget-container\"><p><strong>Compound 24: <\/strong>This small molecule by Abbvie, has been recently reported as a covalent glutathione peroxidase 4 (GPX4) inhibitor, which induces a special type of iron-dependent cell death known as Ferroptosis. GPX4 plays critical roles in lipid peroxidation, the formation of phospholipid hydroperoxides (PLOOH) along with the accumulation of reactive oxygen species (ROS). This molecule uses a reactive chloroacetamide electrophile, targeting a unique selenocysteine (Se) nucleophile within the GPX4 active site. A cell viability EC<sub>50<\/sub> of 117 nM was reported, with a half-life in <em>h<\/em>Plasma of 14 hrs. Against GSH, a half-life of 1.3 hrs was found. Pharmacokinetic studies (100 mg\/kg), found a C<sub>Max<\/sub> value of 5.31 \u00b5g\/mL, a PAMPA score of 3.1, and aqueous solubility of 13.8 \u00b5M (at pH 7). Target engagement with kidney GPX4 was found, along with the induction of relevant PD markers in SCID\/Beige mice models.<\/p><p><strong>Reference: <\/strong><a href=\"https:\/\/doi.org\/10.1021\/acs.jmedchem.2c01415\" target=\"_blank\" rel=\"noopener\"><strong>https:\/\/doi.org\/10.1021\/acs.jmedchem.2c01415<\/strong><\/a><\/p><\/div><\/div><\/div><\/div><\/div><\/section>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-c839ef1 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"c839ef1\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-cb2f3ee jltma-glass-effect-no\" data-id=\"cb2f3ee\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-5d1148b jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"5d1148b\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-c839ef1 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"c839ef1\" data-element_type=\"section\"><div class=\"elementor-container elementor-column-gap-default\"><div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-cb2f3ee jltma-glass-effect-no\" data-id=\"cb2f3ee\" data-element_type=\"column\"><div class=\"elementor-widget-wrap elementor-element-populated\"><div class=\"elementor-element elementor-element-5d1148b jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"5d1148b\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\"><div class=\"elementor-widget-container\"><h2><strong>Compound 28.1<\/strong><\/h2><\/div><\/div><\/div><\/div><\/div><\/section>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-113cca6 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"113cca6\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-f26cbd4 jltma-glass-effect-no\" data-id=\"f26cbd4\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-53246b6 jltma-glass-effect-no elementor-widget elementor-widget-image\" data-id=\"53246b6\" data-element_type=\"widget\" data-widget_type=\"image.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t\t\t\t<figure class=\"wp-caption\">\n\t\t\t\t\t\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/dalriadatx.com\/wp-content\/uploads\/elementor\/thumbs\/Compound-28.1-q3bgcxmhfszgf3n6nxwg6aogbvn3tuff4qm3dqz044.jpg\" title=\"Compound 28.1\" alt=\"Compound 28.1\" loading=\"lazy\" \/>\t\t\t\t\t\t\t\t\t\t\t<figcaption class=\"widget-image-caption wp-caption-text\">Compound 28.1<\/figcaption>\n\t\t\t\t\t\t\t\t\t\t<\/figure>\n\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-6d5c75b elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"6d5c75b\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-404490c jltma-glass-effect-no\" data-id=\"404490c\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-5bd1fae jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"5bd1fae\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-691f658 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"691f658\" data-element_type=\"section\"><div class=\"elementor-container elementor-column-gap-default\"><div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-ff9c429 jltma-glass-effect-no\" data-id=\"ff9c429\" data-element_type=\"column\"><div class=\"elementor-widget-wrap elementor-element-populated\"><div class=\"elementor-element elementor-element-fcb040d jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"fcb040d\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\"><div class=\"elementor-widget-container\"><p><strong>Compound 28.1: <\/strong>In this article, a class of 2-aminopyrimidines were found to be agonists of the bitter taste receptor (TAS2R14), out of which compound 28.1 was highlighted. TAS2R14 is a GPCR and bitter taste receptor found on the tongue, and airway passages with roles in bronchodilation. This allows it to find utility as a potential drug target for asthma and chronic obstructive pulmonary disease (COPD). Inhibitor design followed a scaffold-hopping strategy from Flufenamic acid, an NSAID clinical standard. Compound 28.1 found a TAS2R14 activation EC<sub>50<\/sub> of 72 nM, with an E<sub>Max<\/sub> of 129% (relative to the standard). Molecular docking studies predict useful pi-pi stacking interactions between the tetrazole motif and Trp89, Phe186, and Phe243. Against a panel of 24 non-bitter taste receptors, this molecule was selective for TAS2R14.<\/p><p><strong>Reference: <\/strong><a href=\"https:\/\/doi.org\/10.1021\/acs.jmedchem.2c01997\" target=\"_blank\" rel=\"noopener\"><strong>https:\/\/doi.org\/10.1021\/acs.jmedchem.2c01997<\/strong><\/a><\/p><\/div><\/div><\/div><\/div><\/div><\/section>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-dd7e8a2 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"dd7e8a2\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-7687991 jltma-glass-effect-no\" data-id=\"7687991\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-1c8a196 jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"1c8a196\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-dd7e8a2 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"dd7e8a2\" data-element_type=\"section\"><div class=\"elementor-container elementor-column-gap-default\"><div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-7687991 jltma-glass-effect-no\" data-id=\"7687991\" data-element_type=\"column\"><div class=\"elementor-widget-wrap elementor-element-populated\"><div class=\"elementor-element elementor-element-1c8a196 jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"1c8a196\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\"><div class=\"elementor-widget-container\"><h2><strong>CVN636<\/strong><\/h2><\/div><\/div><\/div><\/div><\/div><\/section>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-193ac36 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"193ac36\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-a362edb jltma-glass-effect-no\" data-id=\"a362edb\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-70e8d19 jltma-glass-effect-no elementor-widget elementor-widget-image\" data-id=\"70e8d19\" data-element_type=\"widget\" data-widget_type=\"image.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t\t\t\t<figure class=\"wp-caption\">\n\t\t\t\t\t\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/dalriadatx.com\/wp-content\/uploads\/elementor\/thumbs\/CVN636--q3bgcykbmn0qqpltigb2qsfwx9ih1jj5gv9kv0xlxw.jpg\" title=\"CVN636\" alt=\"CVN636\" loading=\"lazy\" \/>\t\t\t\t\t\t\t\t\t\t\t<figcaption class=\"widget-image-caption wp-caption-text\">CVN636<\/figcaption>\n\t\t\t\t\t\t\t\t\t\t<\/figure>\n\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-4b1c729 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"4b1c729\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-42a9042 jltma-glass-effect-no\" data-id=\"42a9042\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-40cac09 jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"40cac09\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-691f658 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"691f658\" data-element_type=\"section\"><div class=\"elementor-container elementor-column-gap-default\"><div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-ff9c429 jltma-glass-effect-no\" data-id=\"ff9c429\" data-element_type=\"column\"><div class=\"elementor-widget-wrap elementor-element-populated\"><div class=\"elementor-element elementor-element-fcb040d jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"fcb040d\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\"><div class=\"elementor-widget-container\"><p><strong>CVN636: <\/strong>This chromane scaffold out of Ceravance (and Takeda) has been reported as an allosteric agonist of the metabotropic glutamate receptor 7 (mGluR<sub>7<\/sub>). This glutamate receptor is abundantly expressed across the central nervous system, as well as pre-synaptic glutamatergic, and GABAergic terminals. Starting with a high through-put screen of 650K analogs, followed by 3 rounds of structural optimization, CVN636 was reported as a CNS-penetrant molecule, with an EC<sub>50<\/sub> of 7 nM (cAMP assay). This molecule has a MW of 377 g\/mol, a PSA of 72.5 \u00c5<sup>2<\/sup> and a cLogP of 2.06. <em>In vivo<\/em> PK studies (at 3 mg\/kg, p.o.) revealed a half-life of 2.25 hrs, with a T<sub>Max<\/sub> of 0.67 hrs, and a C<sub>Max<\/sub> of 1.24 \u00b5M. Oral bioavailability was also observed (<em>F <\/em>% = 24 %). In an efficacy study, CVN636 reduced ethanol self-administration in msP rats (<em>in vivo<\/em>).<\/p><p><strong>Reference: <\/strong><a href=\"https:\/\/doi.org\/10.1021\/acsmedchemlett.2c00529\" target=\"_blank\" rel=\"noopener\"><strong>https:\/\/doi.org\/10.1021\/acsmedchemlett.2c00529<\/strong><\/a><\/p><\/div><\/div><\/div><\/div><\/div><\/section>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-8a703aa elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"8a703aa\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-44a6b10 jltma-glass-effect-no\" data-id=\"44a6b10\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-d25d3a3 jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"d25d3a3\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-8a703aa elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"8a703aa\" data-element_type=\"section\"><div class=\"elementor-container elementor-column-gap-default\"><div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-44a6b10 jltma-glass-effect-no\" data-id=\"44a6b10\" data-element_type=\"column\"><div class=\"elementor-widget-wrap elementor-element-populated\"><div class=\"elementor-element elementor-element-d25d3a3 jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"d25d3a3\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\"><div class=\"elementor-widget-container\"><h2><strong>Compound 19<\/strong><\/h2><\/div><\/div><\/div><\/div><\/div><\/section>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-d8c5720 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"d8c5720\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-400f980 jltma-glass-effect-no\" data-id=\"400f980\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-e22794f jltma-glass-effect-no elementor-widget elementor-widget-image\" data-id=\"e22794f\" data-element_type=\"widget\" data-widget_type=\"image.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t\t\t\t<figure class=\"wp-caption\">\n\t\t\t\t\t\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/dalriadatx.com\/wp-content\/uploads\/elementor\/thumbs\/Compound-19-q3bgd2bodz5w15gcwhxl0rhraszxwby2tdvis4s190.jpg\" title=\"Compound 19\" alt=\"Compound 19\" loading=\"lazy\" \/>\t\t\t\t\t\t\t\t\t\t\t<figcaption class=\"widget-image-caption wp-caption-text\">Compound 19<\/figcaption>\n\t\t\t\t\t\t\t\t\t\t<\/figure>\n\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-d522f80 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"d522f80\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-3f5a9c9 jltma-glass-effect-no\" data-id=\"3f5a9c9\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-2203579 jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"2203579\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-691f658 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"691f658\" data-element_type=\"section\"><div class=\"elementor-container elementor-column-gap-default\"><div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-ff9c429 jltma-glass-effect-no\" data-id=\"ff9c429\" data-element_type=\"column\"><div class=\"elementor-widget-wrap elementor-element-populated\"><div class=\"elementor-element elementor-element-fcb040d jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"fcb040d\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\"><div class=\"elementor-widget-container\"><p><strong>Compound 19: <\/strong>Incyte has recently reported this pyrazolo[4,3-d]pyrimidine as an inhibitor of the fibroblast growth factor receptor tyrosine kinase. FGFR kinases play critical roles in in PLC\u03b3, PI3K-AKT, and RAS-MAPK signaling, with pervasive downstream roles in the incidence and progression of human cancers. Inhibitor design followed a scaffold-hopping strategy, by re-purposing a known ALK inhibitor. The initial hit identified demonstrated a FGFR3 IC<sub>50<\/sub> of 266 nM. Structural optimization led to a molecule with an IC<sub>50<\/sub> against FGFR1,2,3,4 of 27, 1.8, 2.0, and 157 nM (selective for FGFR2\/FGFR3, 14-79x FS). In cells, against FGFR2 KATOIII, and IC<sub>50<\/sub> of 24 nM was found, while against BaF3, and V555L, IC<sub>50<\/sub> values of 16, and 1.5 nM were observed. Pharmacokinetics (cyno, at 3 mg\/kg, p.o.) found a half-life of 3.2 hrs, with a C<sub>Max<\/sub> of 825 nM, and an oral bioavailability <em>F <\/em>% of 20%.<\/p><p><strong>Reference: <\/strong><a href=\"https:\/\/doi.org\/10.1021\/acsmedchemlett.3c00003\" target=\"_blank\" rel=\"noopener\"><strong>https:\/\/doi.org\/10.1021\/acsmedchemlett.3c00003<\/strong><\/a><\/p><\/div><\/div><\/div><\/div><\/div><\/section>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-25da639 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"25da639\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-648a628 jltma-glass-effect-no\" data-id=\"648a628\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-a6b2bdc jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"a6b2bdc\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-8a703aa elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"8a703aa\" data-element_type=\"section\"><div class=\"elementor-container elementor-column-gap-default\"><div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-44a6b10 jltma-glass-effect-no\" data-id=\"44a6b10\" data-element_type=\"column\"><div class=\"elementor-widget-wrap elementor-element-populated\"><div class=\"elementor-element elementor-element-d25d3a3 jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"d25d3a3\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\"><div class=\"elementor-widget-container\"><h2><strong>Compound 35i<\/strong><\/h2><\/div><\/div><\/div><\/div><\/div><\/section>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-df7090c elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"df7090c\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-c68fd7b jltma-glass-effect-no\" data-id=\"c68fd7b\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-27a41c7 jltma-glass-effect-no elementor-widget elementor-widget-image\" data-id=\"27a41c7\" data-element_type=\"widget\" data-widget_type=\"image.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t\t\t\t<figure class=\"wp-caption\">\n\t\t\t\t\t\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/dalriadatx.com\/wp-content\/uploads\/elementor\/thumbs\/Compound-35i-q3bgczi5th212bkgcyppba7dindu98mvszx2caw7ro.jpg\" title=\"Compound 35i\" alt=\"Compound 35i\" loading=\"lazy\" \/>\t\t\t\t\t\t\t\t\t\t\t<figcaption class=\"widget-image-caption wp-caption-text\">Compound 35i<\/figcaption>\n\t\t\t\t\t\t\t\t\t\t<\/figure>\n\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-8b1f017 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"8b1f017\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-66bc73e jltma-glass-effect-no\" data-id=\"66bc73e\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-41e6d55 jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"41e6d55\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-691f658 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"691f658\" data-element_type=\"section\"><div class=\"elementor-container elementor-column-gap-default\"><div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-ff9c429 jltma-glass-effect-no\" data-id=\"ff9c429\" data-element_type=\"column\"><div class=\"elementor-widget-wrap elementor-element-populated\"><div class=\"elementor-element elementor-element-fcb040d jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"fcb040d\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\"><div class=\"elementor-widget-container\"><p><strong>Compound 35i: <\/strong>This 3-substituted indazole has been reported as an androgen receptor (AR) antagonist, with medicinal use in prostate cancer. Inhibitor design strategy involved a metabolism-guided approach, improving the metabolic stability of a previously identified first-in-class <em>indole<\/em> AR antagonist via the use of blocking groups. Metabolic soft spots were identified as the 2,3 positions of the indole core-scaffold. As an AR antagonist, an IC<sub>50<\/sub> of 21 nM was found, with no binding to AR LBD (K<sub>i<\/sub> &gt; 100 \u00b5M) and a weak degradation profile. <em>In vitro<\/em> stability studies in MLM revealed a half-life of 120.6 mins (10-fold improvement) and an intrinsic clearance of 0.6 mL\/min\/kg (9-fold improvement). Analogs of this scaffold were shown to display <em>in vivo<\/em> AR antagonism using a Hershberger assay.<\/p><p><strong>Reference: <\/strong><a href=\"https:\/\/doi.org\/10.1021\/acs.jmedchem.2c01858\" target=\"_blank\" rel=\"noopener\"><strong>https:\/\/doi.org\/10.1021\/acs.jmedchem.2c01858<\/strong><\/a><\/p><\/div><\/div><\/div><\/div><\/div><\/section>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-7242c3f elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"7242c3f\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-52272b7 jltma-glass-effect-no\" data-id=\"52272b7\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-65e6aa8 jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"65e6aa8\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-8a703aa elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"8a703aa\" data-element_type=\"section\"><div class=\"elementor-container elementor-column-gap-default\"><div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-44a6b10 jltma-glass-effect-no\" data-id=\"44a6b10\" data-element_type=\"column\"><div class=\"elementor-widget-wrap elementor-element-populated\"><div class=\"elementor-element elementor-element-d25d3a3 jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"d25d3a3\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\"><div class=\"elementor-widget-container\"><h2><strong>YL5084<\/strong><\/h2><\/div><\/div><\/div><\/div><\/div><\/section>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-a997778 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"a997778\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-d0f7877 jltma-glass-effect-no\" data-id=\"d0f7877\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-b7a6a59 jltma-glass-effect-no elementor-widget elementor-widget-image\" data-id=\"b7a6a59\" data-element_type=\"widget\" data-widget_type=\"image.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t\t\t\t<figure class=\"wp-caption\">\n\t\t\t\t\t\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/dalriadatx.com\/wp-content\/uploads\/elementor\/thumbs\/YL5084-q3bgczi5th212bkgcyppba7dindu98mvszx2caw7ro.jpg\" title=\"YL5084\" alt=\"YL5084\" loading=\"lazy\" \/>\t\t\t\t\t\t\t\t\t\t\t<figcaption class=\"widget-image-caption wp-caption-text\">YL5084<\/figcaption>\n\t\t\t\t\t\t\t\t\t\t<\/figure>\n\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-2b3e2ae elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"2b3e2ae\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-9c5ff79 jltma-glass-effect-no\" data-id=\"9c5ff79\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-5f442fd jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"5f442fd\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-691f658 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"691f658\" data-element_type=\"section\"><div class=\"elementor-container elementor-column-gap-default\"><div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-ff9c429 jltma-glass-effect-no\" data-id=\"ff9c429\" data-element_type=\"column\"><div class=\"elementor-widget-wrap elementor-element-populated\"><div class=\"elementor-element elementor-element-fcb040d jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"fcb040d\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\"><div class=\"elementor-widget-container\"><p><strong>YL5084:<\/strong> This molecule out of the Gray lab in Stanford has been reported as a covalent inhibitor of c-Jun <em>N-<\/em>terminal protein kinase (JNK), targeting Cys116 via a canonical 1,4-conjugated acrylamide electrophile (carrying the increasingly popular dimethylamino-handle). JNK kinases, as part of the MAPK pathway involve 3 isoforms: JNK1 (implicated in apoptosis), JNK2 (implicated in cell survival), and JNK3 (roles in the central nervous system). Against JNK1, JNK2, and JNK3, IC<sub>50<\/sub> values of 2173, 70, and 84 nM were reported (this represents 30-fold selectivity for JNK2, over JNK1). With regards to covalent potency against JNK1, and JNK2, <em>k<\/em><sub>inact<\/sub>\/K<sub>i<\/sub> values of 335 and 7166 M<sup>-1<\/sup>s<sup>-1 <\/sup>were reported. Anti-proliferative activity was observed <em>in cellulo<\/em> along with the induction of apoptosis in MM cells in a JNK-2 dependent manner.<\/p><p><strong>Reference: <\/strong><a href=\"https:\/\/doi.org\/10.1021\/acs.jmedchem.2c01834\" target=\"_blank\" rel=\"noopener\"><strong>https:\/\/doi.org\/10.1021\/acs.jmedchem.2c01834<\/strong><\/a><\/p><\/div><\/div><\/div><\/div><\/div><\/section>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-4dc8a65 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"4dc8a65\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-f8dac43 jltma-glass-effect-no\" data-id=\"f8dac43\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-4dad51f jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"4dad51f\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-8a703aa elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"8a703aa\" data-element_type=\"section\"><div class=\"elementor-container elementor-column-gap-default\"><div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-44a6b10 jltma-glass-effect-no\" data-id=\"44a6b10\" data-element_type=\"column\"><div class=\"elementor-widget-wrap elementor-element-populated\"><div class=\"elementor-element elementor-element-d25d3a3 jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"d25d3a3\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\"><div class=\"elementor-widget-container\"><h2><strong>Compound 17b<\/strong><\/h2><\/div><\/div><\/div><\/div><\/div><\/section>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-71f53cf elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"71f53cf\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-3378d2e jltma-glass-effect-no\" data-id=\"3378d2e\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-d069512 jltma-glass-effect-no elementor-widget elementor-widget-image\" data-id=\"d069512\" data-element_type=\"widget\" data-widget_type=\"image.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t\t\t\t<figure class=\"wp-caption\">\n\t\t\t\t\t\t\t\t\t\t<img decoding=\"async\" src=\"https:\/\/dalriadatx.com\/wp-content\/uploads\/elementor\/thumbs\/Compound-17b-q3bgd1du754lpjhq1ziyg9qapf4komuch981autff8.jpg\" title=\"Compound 17b\" alt=\"Compound 17b\" loading=\"lazy\" \/>\t\t\t\t\t\t\t\t\t\t\t<figcaption class=\"widget-image-caption wp-caption-text\">Compound 17b<\/figcaption>\n\t\t\t\t\t\t\t\t\t\t<\/figure>\n\t\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-fb9fcda elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"fb9fcda\" data-element_type=\"section\">\n\t\t\t\t\t\t<div class=\"elementor-container elementor-column-gap-default\">\n\t\t\t\t\t<div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-f2022ed jltma-glass-effect-no\" data-id=\"f2022ed\" data-element_type=\"column\">\n\t\t\t<div class=\"elementor-widget-wrap elementor-element-populated\">\n\t\t\t\t\t\t<div class=\"elementor-element elementor-element-dc35d5a jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"dc35d5a\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\">\n\t\t\t\t<div class=\"elementor-widget-container\">\n\t\t\t\t\t\t\t<section class=\"has_ma_el_bg_slider elementor-section elementor-top-section elementor-element elementor-element-691f658 elementor-section-boxed elementor-section-height-default elementor-section-height-default jltma-glass-effect-no\" data-id=\"691f658\" data-element_type=\"section\"><div class=\"elementor-container elementor-column-gap-default\"><div class=\"has_ma_el_bg_slider elementor-column elementor-col-100 elementor-top-column elementor-element elementor-element-ff9c429 jltma-glass-effect-no\" data-id=\"ff9c429\" data-element_type=\"column\"><div class=\"elementor-widget-wrap elementor-element-populated\"><div class=\"elementor-element elementor-element-fcb040d jltma-glass-effect-no elementor-widget elementor-widget-text-editor\" data-id=\"fcb040d\" data-element_type=\"widget\" data-widget_type=\"text-editor.default\"><div class=\"elementor-widget-container\"><p><strong>Compound 17b: <\/strong>This 3,5-diaryl-1H-pyrazol-urea based small molecule has been reported as a RET kinase inhibitor. Inhibitor design followed a ligand-based design strategy, using a scaffold-hoping approach from a previously identified FLT inhibitor, towards a potent RET binder, with high affinity (RET K<sub>d<\/sub> = 6.5 nM). In cells, against BaF3 an IC<sub>50<\/sub> of 3870 nM was observed, however against BaF3-CCD6-RET, this value went down to 13.6 nM. Against various BaF3-RET mutants (V804M, G819C), IC<sub>50<\/sub> values of 12.1 and 84.6 nM were found. In a Kinome screen against a panel of 468 kinases, the only targets with IC<sub>50<\/sub> &lt; 100 nM were RET, DDR1, KIT, and PDGFRB. Cell target engagement was also confirmed, with activity against RET signalling (BaF3-CCD6-RET cells). <em>In vivo<\/em> PK analysis (at 25 mg\/kg, p.o.) revealed a half-life of 12.4 hrs, a T<sub>Max<\/sub> of 6.7 hrs, and an oral bioavailability (<em>F<\/em> %) of 21.1%.<\/p><p><strong>Reference: <\/strong><a href=\"https:\/\/doi.org\/10.1016\/j.ejmech.2023.115237\" target=\"_blank\" rel=\"noopener\"><strong>https:\/\/doi.org\/10.1016\/j.ejmech.2023.115237<\/strong><\/a><\/p><\/div><\/div><\/div><\/div><\/div><\/section>\t\t\t\t\t\t<\/div>\n\t\t\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/div>\n\t\t\t\t\t<\/div>\n\t\t<\/section>\n\t\t\t\t<\/div>\n\t\t","protected":false},"excerpt":{"rendered":"<p>This issue highlights 8 small molecules reported in recent medicinal chemistry literature, out of the Journal of Medicinal Chemistry, ACS Medicinal Chemistry Letters, and the European Journal of Medicinal Chemistry. Interestingly, several unique scaffolds are represented by this list of compounds, including indazoles, pyrimidines, chromanes, and urea pyrazoles. These small molecules also present several MOAs [&hellip;]<\/p>\n","protected":false},"author":2,"featured_media":6550,"menu_order":0,"template":"","format":"standard","articles_folder":[],"_links":{"self":[{"href":"https:\/\/dalriadatx.com\/wp-json\/wp\/v2\/articles\/6553"}],"collection":[{"href":"https:\/\/dalriadatx.com\/wp-json\/wp\/v2\/articles"}],"about":[{"href":"https:\/\/dalriadatx.com\/wp-json\/wp\/v2\/types\/articles"}],"author":[{"embeddable":true,"href":"https:\/\/dalriadatx.com\/wp-json\/wp\/v2\/users\/2"}],"version-history":[{"count":4,"href":"https:\/\/dalriadatx.com\/wp-json\/wp\/v2\/articles\/6553\/revisions"}],"predecessor-version":[{"id":7289,"href":"https:\/\/dalriadatx.com\/wp-json\/wp\/v2\/articles\/6553\/revisions\/7289"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/dalriadatx.com\/wp-json\/wp\/v2\/media\/6550"}],"wp:attachment":[{"href":"https:\/\/dalriadatx.com\/wp-json\/wp\/v2\/media?parent=6553"}],"wp:term":[{"taxonomy":"articles_folder","embeddable":true,"href":"https:\/\/dalriadatx.com\/wp-json\/wp\/v2\/articles_folder?post=6553"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}