Small Molecule Disruptors of the Glucokinase-Glucokinase Regulatory Protein Interaction: 1. Discovery of a Novel Tool Compound for in Vivo Proof-of-Concept

被引：30

作者：

Ashton, Kate S. ^{[1
]}

Andrews, Kristin L. ^{[2
]}

Bryan, Marion C. ^{[1
]}

Chen, Jie ^{[5
]}

Chen, Kui ^{[2
]}

Chen, Michelle ^{[4
]}

Chmait, Samer ^{[2
]}

Croghan, Michael ^{[1
]}

Cupples, Rod ^{[4
]}

Fotsch, Christopher ^{[1
]}

Helmering, Joan ^{[4
]}

Jordan, Steve R. ^{[2
]}

Kurzeja, Robert J. M. ^{[3
]}

Michelsen, Klaus ^{[2
]}

Pennington, Lewis D. ^{[1
]}

Poon, Steve F. ^{[1
]}

Sivits, Glenn ^{[4
]}

Van, Gwyneth ^{[6
]}

Vonderfecht, Steve L. ^{[6
]}

Wahl, Robert C. ^{[1
]}

Zhang, Jiandong ^{[2
]}

Lloyd, David J. ^{[4
]}

Hale, Clarence ^{[4
]}

St Jean, David J., Jr. ^{[1
]}

机构：

[1] Amgen Inc, Dept Therapeut Discovery Med Chem, Thousand Oaks, CA 91320 USA

[2] Amgen Inc, Dept Therapeut Discovery Mol Struct & Characteriz, Thousand Oaks, CA 91320 USA

[3] Amgen Inc, Dept Therapeut Discovery Prot Technol, Thousand Oaks, CA 91320 USA

[4] Amgen Inc, Dept Metab Disorders, Thousand Oaks, CA 91320 USA

[5] Amgen Inc, Dept Pharmacokinet & Drug Metab, Thousand Oaks, CA 91320 USA

[6] Amgen Inc, Dept Pathol, Thousand Oaks, CA 91320 USA

来源：

JOURNAL OF MEDICINAL CHEMISTRY | 2014年 / 57卷 / 02期

关键词：

LIVER GLUCOKINASE; DIABETES THERAPY; ACTIVATORS; MECHANISM; DRUG;

D O I：

10.1021/jm4016735

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

Small molecule activators of glucokinase have shown robust efficacy in both preclinical models and humans. However, overactivation of glucokinase (GK) can cause excessive glucose turnover, leading to hypoglycemia. To circumvent this adverse side effect, we chose to modulate GK activity by targeting the endogenous inhibitor of GK, glucokinase regulatory protein (GKRP). Disrupting the GK-GKRP complex results in an increase in the amount of unbound cytosolic GK without altering the inherent kinetics of the enzyme. Herein we report the identification of compounds that efficiently disrupt the GK-GKRP interaction via a previously unknown binding pocket. Using a structure-based approach, the potency of the initial hit was improved to provide 25 (AMG-1694). When dosed in ZDF rats, 25 showed both a robust pharmacodynamic effect as well as a statistically significant reduction in glucose. Additionally,. hypoglycemia was not observed in either the hyperglycemic or normal rats.

引用

页码：309 / 324

页数：16

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