Identification and biological activity of 6-alkyl-substituted 3-methyl-pyridine-2-carbonyl amino dimethyl-benzoic acid EP4 antagonists

详细信息    查看全文

• 作者：Maria-Jesus Blanco ; ^{blanco_maria@lilly.com" class="auth_mail" title="E-mail the corresponding author} ; Tatiana Vetman ; Srinivasan Chandrasekhar ; Matthew J. Fisher ; Anita Harvey ; Steven L. Kuklish ; Mark Chambers ; Chaohua Lin ; Daniel Mudra ; Jennifer Oskins ; Xu-Shan Wang ; Xiao-Peng Yu ; Alan M. Warshawsky
• 关键词：Prostaglandin E2 (PGE2) ; EP4 antagonist ; Clinical candidate ; Pain ; Inflammation
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 May 2016
• 年：2016
• 卷：26
• 期：9
• 页码：2303-2307
• 全文大小：1237 K

文摘

Continued SAR optimization of a series of 3-methylpyridine-2-carbonyl amino-2,4-dimethyl-benzoic acid led to the selection of compound 4f for clinical studies. Compound 4f showed an IC₅₀ of 123 nM for inhibition of PGE2-induced TNFα reduction in an ex vivo LPS-stimulated human whole blood assay (showing >10-fold increase over clinical compound CJ-023,423). Pharmacokinetic profile, selectivity and in vivo efficacy comparing 4f to NSAID diclofenac in the monoiodoacetic acid (MIA) pain model and adjuvant induced arthritis (AIA) inflammatory model are included.