Discovery of 6-(Aminomethyl)-5-(2,4-dichlorophenyl)-7-methylimidazo[1,2-a]pyrimidine-2-carboxamides as Potent, Selective Dipeptidyl Peptidase-4 (DPP4) Inhibitors

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• 作者：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
• 刊名：Journal of Medicinal Chemistry
• 出版年：2010
• 出版时间：August 12, 2010
• 年：2010
• 卷：53
• 期：15
• 页码：5620-5628
• 全文大小：915K
• 年卷期：v.53,no.15(August 12, 2010)
• ISSN：1520-4804

文摘

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--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.