Design, Synthesis, and Biological Activity of Potent and Orally Available G Protein-Coupled Receptor 40 Agonists

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• 作者：Shinobu Sasaki ; Shuji Kitamura ; Nobuyuki Negoro ; Masami Suzuki ; Yoshiyuki Tsujihata ; Nobuhiro Suzuki ; Takashi Santou ; Naoyuki Kanzaki ; Masataka Harada ; Yasuhiro Tanaka ; Makoto Kobayashi ; Norio Tada ; Miyuki Funami ; Toshimasa Tanaka ; Yoshio Yamamoto ; Kohji Fukatsu ; Tsuneo Yasuma ; Yu Momose
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：March 10, 2011
• 年：2011
• 卷：54
• 期：5
• 页码：1365-1378
• 全文大小：1141K
• 年卷期：v.54,no.5(March 10, 2011)
• ISSN：1520-4804

文摘

G protein-coupled receptor 40 (GPR40) is being recently considered to be a new potential drug target for the treatment of type 2 diabetes because of its role in the enhancement of free fatty acid-regulated glucose-stimulated insulin secretion in pancreatic 尾-cells. We initially identified benzyloxyphenylpropanoic acid (1b) (EC₅₀ = 510 nM), which was designed based on the structure of free fatty acids, as a promising lead compound with GPR40 agonist activity. Chemical modification of compound 1b led to the discovery of 3-{4-[(2鈥?6鈥?dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid (4p) as a potent GPR40 agonist (EC₅₀ = 5.7 nM). Compound 4p exhibited acceptable pharmacokinetic profiles and significant glucose-lowering effects during an oral glucose tolerance test in diabetic rats. Moreover, no hypoglycemic event was observed even after administration of a high dose of compound 4p to normal fasted rats. These pharmacological results suggest that GPR40 agonists might be novel glucose-dependent insulin secretagogues with little or no risk of hypoglycemia.