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Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394.

ABSTRACT: Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure-activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes.

SUBMITTER: Dransfield PJ

PROVIDER: S-EPMC4948016 | biostudies-literature | 2016 Jul

REPOSITORIES: biostudies-literature

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Novel Series of Potent Glucokinase Activators Leading to the Discovery of AM-2394.

Dransfield Paul J PJ Pattaropong Vatee V Lai Sujen S Fu Zice Z Kohn Todd J TJ Du Xiaohui X Cheng Alan A Xiong Yumei Y Komorowski Renee R Jin Lixia L Conn Marion M Tien Eric E DeWolf Walter E WE Hinklin Ronald J RJ Aicher Thomas D TD Kraser Christopher F CF Boyd Steven A SA Voegtli Walter C WC Condroski Kevin R KR Veniant-Ellison Murielle M Medina Julio C JC Houze Jonathan J Coward Peter P

ACS medicinal chemistry letters 20160523 7

Glucokinase (GK) catalyzes the phosphorylation of glucose to glucose-6-phosphate. We present the structure-activity relationships leading to the discovery of AM-2394, a structurally distinct GKA. AM-2394 activates GK with an EC50 of 60 nM, increases the affinity of GK for glucose by approximately 10-fold, exhibits moderate clearance and good oral bioavailability in multiple animal models, and lowers glucose excursion following an oral glucose tolerance test in an ob/ob mouse model of diabetes. ...[more]

PMID: 27437083

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