Referenced in: none

Automatically associated channels: Kv11.1

Title: Discovery of 6-(aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamides as potent, selective dipeptidyl peptidase-4 (DPP4) inhibitors.

Authors: Wei Meng, Robert P Brigance, Hannguang J Chao, Aberra Fura, Thomas Harrity, Jovita Marcinkeviciene, Stephen P O'Connor, James K Tamura, Dianlin Xie, Yaqun Zhang, Herbert E Klei, Kevin Kish, Carolyn A Weigelt, Huji Turdi, Aiying Wang, Robert Zahler, Mark S Kirby, Lawrence G Hamann

Journal, date & volume: J. Med. Chem., 2010 Aug 12 , 53, 5620-8

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/20684603

Abstract
Continued structure-activity relationship (SAR) exploration within our previously disclosed azolopyrimidine containing dipeptidyl peptidase-4 (DPP4) inhibitors led us to focus on an imidazolopyrimidine series in particular. Further study revealed that by replacing the aryl substitution on the imidazole ring with a more polar carboxylic ester or amide, these compounds displayed not only increased DPP4 binding activity but also significantly reduced human ether-a-go-go related gene (hERG) and sodium channel inhibitory activities. Additional incremental adjustment of polarity led to permeable molecules which exhibited favorable pharmacokinetic (PK) profiles in preclinical animal species. The active site binding mode of these compounds was determined by X-ray crystallography as exemplified by amide 24c. A subsequent lead molecule from this series, (+)-6-(aminomethyl)-5-(2,4-dichlorophenyl)-N-(1-ethyl-1H-pyrazol-5-yl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamide (24s), emerged as a potent, selective DPP4 inhibitor that displayed excellent PK profiles and in vivo efficacy in ob/ob mice.