Title of article :
Pyrrolidine-constrained phenethylamines: The design of potent, selective, and pharmacologically efficacious dipeptidyl peptidase IV (DPP4) inhibitors from a lead-like screening hit
Author/Authors :
Bradley J. Backes، نويسنده , , Kenton Longenecker، نويسنده , , Gregory L. Hamilton، نويسنده , , Kent Stewart، نويسنده , , Chunqiu Lai، نويسنده , , Hana Kopecka، نويسنده , , Thomas W. von Geldern، نويسنده , , David J. Madar، نويسنده , , Zhonghua Pei، نويسنده , , Thomas H. Lubben، نويسنده , , Bradley A. Zinker، نويسنده , , Zhenping Tian، نويسنده , , Stephen J. Ballaron، نويسنده , , Michael A. Stashko، نويسنده , , Amanda K. Mika، نويسنده , , David W.A. Beno، نويسنده , , Anita J. Kempf-Grote، نويسنده , , Candace Black-Schaefer، نويسنده , , Hing L. Sham، نويسنده , , James M. Trevillyan، نويسنده ,
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 >400× 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.
