Discovery of Novel Tricyclic Full Agonists for the G-Protein-Coupled Niacin Receptor 109A with Minimized Flushing in Rats

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• 作者：Hong C. Shen ; Fa-Xiang Ding ; Qiaolin Deng ; Larissa C. Wilsie ; Mihajlo L. Krsmanovic ; Andrew K. Taggart ; Ester Carballo-Jane ; Ning Ren ; Tian-Quan Cai ; Tsuei-Ju Wu ; Kenneth K. Wu ; Kang Cheng ; Qing Chen
• 刊名：Journal of Medicinal Chemistry
• 出版年：2009
• 出版时间：April 23, 2009
• 年：2009
• 卷：52
• 期：8
• 页码：2587-2602
• 全文大小：449K
• 年卷期：v.52,no.8(April 23, 2009)
• ISSN：1520-4804

文摘

Tricyclic analogues were rationally designed as the high affinity niacin receptor G-protein-coupled receptor 109A (GPR109A) agonists by overlapping three lead structures. Various tricyclic anthranilide and cycloalkene carboxylic acid full agonists were discovered with excellent in vitro activity. Compound 2g displayed a good therapeutic index regarding free fatty acids (FFA) reduction and vasodilation effects in rats, with very weak cytochrome P450 2C8 (CYP2C8) and cytochrome P450 2C9 (CYP2C9) inhibition, and a good mouse pharmacokinetics (PK) profile.