{"id":2432,"date":"2018-02-15T11:24:00","date_gmt":"2018-02-15T11:24:00","guid":{"rendered":"https:\/\/www.sygnaturediscovery.com\/journal-paper\/design-and-synthesis-of-a-potent-highly-selective-orally-bioavailable-retinoic-acid-receptor-alpha-agonist\/"},"modified":"2026-01-30T13:54:42","modified_gmt":"2026-01-30T13:54:42","slug":"design-and-synthesis-of-a-potent-highly-selective-orally-bioavailable-retinoic-acid-receptor-alpha-agonist","status":"publish","type":"journal-paper","link":"https:\/\/www.sygnaturediscovery.com\/fr\/journal-paper\/design-and-synthesis-of-a-potent-highly-selective-orally-bioavailable-retinoic-acid-receptor-alpha-agonist\/","title":{"rendered":"Design and synthesis of a potent, highly selective, orally bioavailable, retinoic acid receptor alpha agonist"},"content":{"rendered":"<p><span class=\"authors-list-item \"><strong>Earl Clarke<\/strong><span class=\"comma\">,<strong>\u00a0<\/strong><\/span><\/span><span class=\"authors-list-item \"><strong>Christopher I Jarvis<\/strong><span class=\"comma\">,\u00a0<\/span><\/span><span class=\"authors-list-item \"><strong>Maria B Goncalves<\/strong><span class=\"comma\">,\u00a0<\/span><\/span><span class=\"authors-list-item \"><strong>S Barret Kalindjian<\/strong><span class=\"comma\">,<strong>\u00a0<\/strong><\/span><\/span><span class=\"authors-list-item \"><strong>David R Adams<\/strong><span class=\"comma\">,\u00a0<\/span><\/span><span class=\"authors-list-item \"><strong>Jane T Brown<\/strong><span class=\"comma\">,\u00a0<\/span><\/span><span class=\"authors-list-item \"><strong>Jason J Shiers<\/strong><span class=\"comma\">,\u00a0<\/span><\/span><span class=\"authors-list-item \"><strong>David M A Taddei<\/strong><span class=\"comma\">,\u00a0<\/span><\/span><span class=\"authors-list-item \"><strong>Elodie Ravier<\/strong>,<span class=\"comma\">\u00a0<\/span><\/span><span class=\"authors-list-item \"><strong>Stephanie Barlow<\/strong><span class=\"comma\">,\u00a0<\/span><\/span><span class=\"authors-list-item \"><strong>Iain Miller<\/strong><span class=\"comma\">,\u00a0<\/span><\/span><span class=\"authors-list-item \"><strong>Vanessa Smith<\/strong><span class=\"comma\">,\u00a0<\/span><\/span><span class=\"authors-list-item \">Alan D Borthwick<span class=\"comma\">,\u00a0<\/span><\/span><span class=\"authors-list-item \"><strong>Jonathan P T Corcoran<\/strong><\/span><\/p>\n<p><strong>Abstract<\/strong><\/p>\n<p>A ligand-based virtual screening exercise examining likely bioactive conformations of AM 580 (2) and AGN 193836 (3) was used to identify the novel, less lipophilic RAR\u03b1 agonist 4-(3,5-dichloro-4-ethoxybenzamido)benzoic acid 5, which has good selectivity over the RAR\u03b2, and RAR\u03b3 receptors. Analysis of the medicinal chemistry parameters of the 3,5-substituents of derivatives of template 5 enabled us to design a class of drug-like molecules with lower intrinsic clearance and higher oral bioavailability which led to the novel RAR\u03b1 agonist 4-(3-chloro-4-ethoxy-5-isopropoxybenzamido)-2-methylbenzoic acid 56 that has high RAR\u03b1 potency and excellent selectivity versus RAR\u03b2 (2 orders of magnitude) and RAR\u03b3 (4 orders of magnitude) at both the human and mouse RAR receptors with improved drug-like properties. This RAR\u03b1 specific agonist 56 has high oral bioavailability (&gt;80%) in both mice and dogs with a good PK profile and was shown to be inactive in cytotoxicity and genotoxicity screens.<\/p>\n<p><strong>Ref:\u00a0<\/strong><a href=\"https:\/\/pubmed.ncbi.nlm.nih.gov\/29288071\/\">Bioorgan Med Chem 2018<\/a><\/p>\n","protected":false},"excerpt":{"rendered":"","protected":false},"featured_media":0,"template":"","category":[682,713],"resource_tag":[],"class_list":["post-2432","journal-paper","type-journal-paper","status-publish","hentry","category-chemistry","category-medicinal-chemistry"],"acf":[],"yoast_head":"<!-- This site is optimized with the Yoast SEO plugin v27.3 - https:\/\/yoast.com\/product\/yoast-seo-wordpress\/ -->\n<title>Design and synthesis of a potent, highly selective, orally bioavailable, retinoic acid receptor alpha agonist - Sygnature<\/title>\n<meta name=\"robots\" content=\"index, follow, max-snippet:-1, max-image-preview:large, max-video-preview:-1\" \/>\n<link rel=\"canonical\" href=\"https:\/\/www.sygnaturediscovery.com\/fr\/journal-paper\/design-and-synthesis-of-a-potent-highly-selective-orally-bioavailable-retinoic-acid-receptor-alpha-agonist\/\" \/>\n<meta property=\"og:locale\" content=\"fr_CA\" \/>\n<meta property=\"og:type\" content=\"article\" \/>\n<meta property=\"og:title\" content=\"Design and synthesis of a potent, highly selective, orally bioavailable, retinoic acid receptor alpha agonist - 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