Investigation of Functionally Liver Selective Glucokinase Activators for the Treatment of Type 2 Diabetes

被引：78

作者：

Bebernitz, Gregory R. ^{[1
]}

Beaulieu, Valerie ^{[1
]}

Dale, Bethany A. ^{[1
]}

Deacon, Richard ^{[1
]}

Duttaroy, Alokesh ^{[1
]}

Gao, Jiaping ^{[1
]}

Grondine, Melissa S. ^{[1
]}

Gupta, Ramesh C. ^{[2
]}

Kakmak, Mesut ^{[1
]}

Kavana, Michael ^{[1
]}

Kirman, Louise C. ^{[1
]}

Liang, Jinsheng ^{[1
]}

Maniara, Wieslawa M. ^{[1
]}

Munshi, Siralee ^{[2
]}

Nadkarni, Sunil S. ^{[2
]}

Schuster, Herbert F. ^{[1
]}

Stams, Travis ^{[1
]}

Denny, Irene St. ^{[1
]}

Taslimi, Paul M. ^{[1
]}

Vash, Brian ^{[1
]}

Caplan, Shari L. ^{[1
]}

机构：

[1] Novartis Inst BioMed Res Inc, Cambridge, MA 02139 USA

[2] Torrent Res Ctr, Village Bhat, Gujarat, India

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2009年 / 52卷 / 19期

关键词：

DISCOVERY; TRANSLOCATION; HEPATOCYTES; THERAPY; AGENTS; ACIDS;

D O I：

10.1021/jm900839k

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Type 2 diabetes is a polygenic disease which afflicts nearly 200 million people worldwide and is expected to increase to near epidemic levels over the next 10-15 years. Glucokinase (GK) activators are currently under investigation by a number of pharmaceutical companies with only a few reaching early clinical evaluation. A GK activator has the promise of potentially affecting both the beta-cells of the pancreas, by improving glucose sensitive insulin secretion, as well as the liver, by reducing uncontrolled glucose output and restoring post-prandial glucose uptake and storage as glycogen. Herein, we report our efforts on a sulfonamide chemotype with the aim to generate liver selective GK activators which culminated in the discovery of 3-cyclopentyl-N-(5-methoxy-thiazolo[5,4-b]pyridin-2-yl)-2-[4-(4-methylpiperazine-1-sulfonyl)-phenyl]-propionamide (17c). This compound activated the GK enzyme (alpha K(a) = 39 nM) in vitro at low nanomolar concentrations and significantly reduced glucose levels during an oral glucose tolerance test in normal mice.

引用

页码：6142 / 6152

页数：11

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