Discovery of an Orally Active and Long-acting DPP-IV Inhibitor through Property-based Optimization with an in silico Biotransformation Prediction Tool.

Long-acting dipeptidyl peptidase IV inhibitors have emerged as promising interventions for type 2 diabetes. The once weekly dosing brings greater patient compliance and more stable glycemic control. Started from our previously disclosed highly potent but severe hepatic biotransformed hit compound with thienoprimidine scaffold, lead compound was rapidly generated by drawing on the experience of our former discovered long-acting compounds bearing pyrrolopyrimidine scaffold. With the aid of an in silico biotransformation prediction tool, (R)-2-((2-(3-aminopiperidin-1-yl)-4-oxo-6-(pyridin-3-yl)thieno[3,2-d]pyrimidin-3(4H)-yl)methyl)-4-fluorobenzonitrile was eventually generated and determined to be with high potency, fine pharmacokinetic profile, and as well as a long-acting in vivo efficacy.