Benzo[b]thiophene-2-carboxamide derivatives as potent urotensin-II receptor antagonists

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• 作者：Chae Jo Lim^a ; ^b ; ^{chemlcj@krict.re.kr" class="auth_mail" title="E-mail the corresponding author} ; Seong Eun Woo^a ; ^b ; Su Ik Ko^a ; ^c ; Byung Ho Lee^a ; Kwang-Seok Oh^a ; ^b ; Kyu Yang Yi^a ; ^b ; ^{kyyi@krict.re.kr" class="auth_mail" title="E-mail the corresponding author}
• 关键词：Urotensin-II receptor ; Antagonists ; Benzo[b]thiophene carboxamide ; Cardiovascular disease
• 刊名：Bioorganic & Medicinal Chemistry Letters
• 出版年：2016
• 出版时间：1 October 2016
• 年：2016
• 卷：26
• 期：19
• 页码：4684-4686
• 全文大小：928 K

文摘

Members of a series of benzo[b]thiophene-2-carboxamide derivatives, possessing an N-(1-(3-bromo-4-(piperidin-4-yloxy)benzyl)piperidin-4-yl) group, were synthesized and evaluated as urotensin-II receptor antagonists. The results show that these substances have potent UT binding affinities. Observations made in a systematic SAR investigation of the effects of a variety of substituents (R¹ and R²) at the 5- and 6-positions in the benzo[b]thiophene-2-carboxamide moiety on UT binding affinities led to identification of the 5-cyano analog 7f as a highly potent UT antagonist with an IC₅₀ value of 25 nM. Despite having a good metabolic stability, 7f is a potent inhibitor of CYP isozyme and displays an unsuitable PK profile.