Structure Report for: 3Q0T

Wang, W., Devasthale, P., Wang, A., Egan, D., Morgan, N., Cap, M., Fura, A., Klei, H.E., Kish, K., Sun, L., Levesque, P., Zahler, R., Kirby, M., Hamann, L.G.

Title: Discovery of 6-(Aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxa mides as Potent, Selective Dipeptidyl Peptidase-4 (DPP4) Inhibitors
Meng W, Brigance RP, Chao HJ, Fura A, Harrity T, Marcinkeviciene J, O'Connor SP, Tamura JK, Xie D and Hamann LG <8 more author(s)> Meng W, Brigance RP, Chao HJ, Fura A, Harrity T, Marcinkeviciene J, O'Connor SP, Tamura JK, Xie D, Zhang Y, Klei HE, Kish K, Weigelt CA, Turdi H, Wang A, Zahler R, Kirby MS, Hamann LG (- 8)
Ref: Journal of Medicinal Chemistry, 53:5620, 2010 : PubMed
Abstract


ESTHER: Meng_2010_J.Med.Chem_53_5620
PubMedSearch: Meng 2010 J.Med.Chem 53 5620
PubMedID: 20684603
Gene_locus related to this paper: human-DPP4
Inhibitor(s) related to this paper: CHEMBL1214943, CHEMBL1910111, CHEMBL1215376

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.