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ID: ALA1777763

Journal: Bioorg Med Chem Lett

Title: Discovery of a nortropanol derivative as a potent and orally active GPR119 agonist for type 2 diabetes.

Authors: Xia Y, Chackalamannil S, Greenlee WJ, Jayne C, Neustadt B, Stamford A, Vaccaro H, Xu XL, Baker H, O'Neill K, Woods M, Hawes B, Kowalski T.

Abstract: The lead optimization studies of a series of GPR119 agonists incorporating a nortropanol scaffold are described. Extensive structure-activity relationship (SAR) studies of the lead compound 20f led to the identification of compound 36j as a potent, single digit nanomolar GPR119 agonist with high agonist activity. Compound 36j was orally active in lowering blood glucose levels in a mouse oral glucose tolerance test and increased plasma insulin levels in a rat hyperglycemic model. It showed good to excellent pharmacokinetic properties in rats and monkeys and no untoward activities in counter-screen assays. Compound 36j demonstrated an attractive in vitro and in vivo profile for further development.

CiteXplore: 21536438

DOI: 10.1016/j.bmcl.2011.04.035