Discovery of a small molecule insulin mimetic with antidiabetic activity in mice

被引：364

作者：

Zhang, B

Salituro, G

Szalkowski, D

Li, ZH

Zhang, Y

Royo, I

Vilella, D

Díez, MT

Pelaez, F

Ruby, C

Kendall, RL

Mao, XZ

Griffin, P

Calaycay, J

Zierath, JR

Heck, JV

Smith, RG

Moller, DE

机构：

[1] Merck Res Labs, Dept Mol Endocrinol, Rahway, NJ 07065 USA

[2] Merck Res Labs, Dept Nat Prod Drug Discovery, Rahway, NJ 07065 USA

[3] Merck Res Labs, Dept Mol Divers & Design, Rahway, NJ 07065 USA

[4] Merck Sharp & Dohme Espana, Ctr Invest Basica, Madrid 28027, Spain

[5] Merck Res Labs, Dept Canc Res, W Point, PA 19486 USA

[6] Karolinska Inst, Karolinska Hosp, Dept Clin Physiol, S-17176 Stockholm, Sweden

来源：

SCIENCE | 1999年 / 284卷 / 5416期

关键词：

D O I：

10.1126/science.284.5416.974

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Insulin elicits a spectrum of biological responses by binding to its cell surface receptor. In a screen for small molecules that activate the human insulin receptor tyrosine kinase, a nonpeptidyl fungal metabolite (L-783,281) was identified that acted as an insulin mimetic in several biochemical and cellular assays. The compound was selective for insulin receptor versus insulin-like growth factor I (IGFI) receptor and other receptor tyrosine kinases. Oral administration of L-783,281 to two mouse models of diabetes resulted in significant Lowering in blood glucose Levels. These results demonstrate the feasibility of discovering novel insulin receptor activators that may Lead to new therapies for diabetes.

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页码：974 / 977

页数：4

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