Optimization of (2,3-Dihydro-1-benzofuran-3-yl)acetic Acids: Discovery of a Non-Free Fatty Acid-Like, Highly Bioavailable G Protein-Coupled Receptor 40/Free Fatty Acid Receptor 1 Agonist as a Glucose-Dependent Insulinotropic Agent

被引：70

作者：

Negoro, Nobuyuki ^{[2
]}

Sasaki, Shinobu ^{[2
]}

Mikami, Satoshi ^{[2
]}

Ito, Masahiro ^{[2
]}

Tsujihata, Yoshiyuki ^{[2
]}

Ito, Ryo ^{[2
]}

Suzuki, Masami ^{[2
]}

Takeuchi, Koji ^{[2
]}

Suzuki, Nobuhiro ^{[1
]}

Miyazaki, Junichi ^{[1
]}

Santou, Takashi ^{[2
]}

Odani, Tomoyuki ^{[2
]}

Kanzaki, Naoyuki ^{[2
]}

Funami, Miyuki ^{[1
]}

Morohashi, Akio ^{[2
]}

Nonaka, Masami ^{[2
]}

Matsunaga, Shinichiro ^{[2
]}

Yasuma, Tsuneo ^{[1
]}

Momose, Yu ^{[2
]}

机构：

[1] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Yodogawa Ku, Osaka 5328686, Japan

[2] Takeda Pharmaceut Co Ltd, Div Pharmaceut Res, Fujisawa, Kanagawa 2518555, Japan

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2012年 / 55卷 / 08期

关键词：

BETA-CELLS; SECRETION; GPR40; TAK-875;

D O I：

10.1021/jm300170m

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) is a free fatty acid (FFA) receptor that mediates FFA-amplified glucose-stimulated insulin secretion in pancreatic beta-cells. We previously identified (2,3-dihydro-1-benzofuran-3-yl)acetic acid derivative 2 as a candidate, but it had relatively high lipophilicity. Adding a polar functional group on 2 yielded several compounds with lower lipophilicity and little effect on caspase-3/7 activity at 30 mu M (a marker of toxicity in human HepG2 hepatocytes). Three optimized compounds showed promising pharmacokinetic profiles with good in vivo effects. Of these, compound 16 had the lowest lipophilicity. Metabolic analysis of 16 showed a long-acting PK profile due to high resistance to beta-oxidation. Oral administration of 16 significantly reduced plasma glucose excursion and increased insulin secretion during an OGTT in type 2 diabetic rats. Compound 16 (TAK-875) is being evaluated in human clinical trials for the treatment of type 2 diabetes.

引用

页码：3960 / 3974

页数：15

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