Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit |
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Authors: | Backes Bradley J Longenecker Kenton Hamilton Gregory L Stewart Kent Lai Chunqiu Kopecka Hana von Geldern Thomas W Madar David J Pei Zhonghua Lubben Thomas H Zinker Bradley A Tian Zhenping Ballaron Stephen J Stashko Michael A Mika Amanda K Beno David W A Kempf-Grote Anita J Black-Schaefer Candace Sham Hing L Trevillyan James M |
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Institution: | Metabolic Disease Research, Abbott Laboratories, Abbott Park Road, Abbott Park, IL 60064-6099, USA. bradley.backes@abbott.com |
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Abstract: | A novel series of pyrrolidine-constrained phenethylamines were developed as dipeptidyl peptidase IV (DPP4) inhibitors for the treatment of type 2 diabetes. The cyclohexene ring of lead-like screening hit 5 was replaced with a pyrrolidine to enable parallel chemistry, and protein co-crystal structural data guided the optimization of N-substituents. Employing this strategy, a >400x improvement in potency over the initial hit was realized in rapid fashion. Optimized compounds are potent and selective inhibitors with excellent pharmacokinetic profiles. Compound 30 was efficacious in vivo, lowering blood glucose in ZDF rats that were allowed to feed freely on a mixed meal. |
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