Discovery, Structure-Activity Relationships, Pharmacokinetics, and Efficacy of Glucokinase Activator (2R)-3-Cyclopentyl-2-(4-methanesulfonylphenyl)-N-thiazol-2-yl-propionamide (RO0281675)

被引：40

作者：

Haynes, Nancy-Ellen ^{[1
]}

Corbett, Wendy L. ^{[1
]}

Bizzarro, Fred T. ^{[1
]}

Guertin, Kevin R. ^{[1
]}

Hilliard, Darryl W. ^{[1
]}

Holland, George W. ^{[1
]}

Kester, Robert F. ^{[1
]}

Mahaney, Paige E. ^{[1
]}

Qi, Lida ^{[1
]}

Spence, Cheryl L. ^{[2
]}

Tengi, John ^{[1
]}

Dvorozniak, Mark T. ^{[2
]}

Railkar, Aruna ^{[3
]}

Matschinsky, Franz M. ^{[4
,5
]}

Grippo, Joseph F. ^{[2
]}

Grimsby, Joseph ^{[2
]}

Sarabu, Ramakanth ^{[1
]}

机构：

[1] Hoffmann La Roche Inc, Dept Discovery Chem, Nutley, NJ 07110 USA

[2] Hoffmann La Roche Inc, Dept Metab & Vasc Dis, Nutley, NJ 07110 USA

[3] Hoffmann La Roche Inc, Dept Non Clin Drug Safety & Discovery Technol, Nutley, NJ 07110 USA

[4] Univ Penn, Sch Med, Dept Biochem, Philadelphia, PA 19104 USA

[5] Univ Penn, Sch Med, Ctr Diabet, Philadelphia, PA 19104 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2010年 / 53卷 / 09期

关键词：

AMIDES;

D O I：

10.1021/jm100039a

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Glucokinase (GK) is a glucose sensor that couples glucose metabolism to insulin release. The important role of GK in maintaining glucose homeostasis is illustrated in patients with GK mutations. In this publication, identification of the hit molecule 1 and its SA R development, which led to the discovery of potent allosteric GK activators 9a and 21a, is described. Compound 21a (RO0281675) was used to validate the clinical relevance of targeting GK to treat type 2 diabetes.

引用

页码：3618 / 3625

页数：8

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