Identification of Fused-Ring Alkanoic Acids with Improved Pharmacokinetic Profiles that Act as G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonists

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• 作者：Nobuyuki Negoro ; Shinobu Sasaki ; Masahiro Ito ; Shuji Kitamura ; Yoshiyuki Tsujihata ; Ryo Ito ; Masami Suzuki ; Koji Takeuchi ; Nobuhiro Suzuki ; Junichi Miyazaki ; Takashi Santou ; Tomoyuki Odani ; Naoyuki Kanzaki ; Miyuki Funami ; Toshimasa Tanaka ; Tsuneo Yasuma ; Yu Momose
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：February 23, 2012
• 年：2012
• 卷：55
• 期：4
• 页码：1538-1552
• 全文大小：699K
• 年卷期：v.55,no.4(February 23, 2012)
• ISSN：1520-4804

文摘

The G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. We previously identified phenylpropanoic acid derivative 1 (3-{4-[(2鈥?6鈥?dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid) as a potent and orally available GPR40/FFA1 agonist; however, 1 exhibited high clearance and low oral bioavailability, which was likely due to its susceptibility to 尾-oxidation at the phenylpropanoic acid moiety. To identify long-acting compounds, we attempted to block the metabolically labile sites at the phenylpropanoic acid moiety by introducing a fused-ring structure. Various fused-ring alkanoic acids with potent GPR40/FFA1 activities and good PK profiles were produced. Further optimizations of the lipophilic portion and the acidic moiety led to the discovery of dihydrobenzofuran derivative 53 ((6-{[4鈥?(2-ethoxyethoxy)-2鈥?6鈥?dimethylbiphenyl-3-yl]methoxy}-2,3-dihydro-1-benzofuran-3-yl)acetic acid), which acted as a GPR40/FFA1 agonist with in vivo efficacy during an oral glucose tolerance test (OGTT) in rats with impaired glucose tolerance.