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  • Title: Discovery of an Orally Active and Long-Acting DPP-IV Inhibitor through Property-Based Optimization with an in Silico Biotransformation Prediction Tool.
    Author: Zeng S, Dou W, Li M, Zhou Y, Guo J, Zhao N, Huang H, Zhou Q, Hu W, Ma Y, Zhao X, Xie H.
    Journal: ChemMedChem; 2020 Aug 19; 15(16):1608-1617. PubMed ID: 32558296.
    Abstract:
    Long-acting dipeptidyl peptidase IV inhibitors have emerged as promising molecules for interventions for type 2 diabetes. Once weekly dosing brings greater patient compliance and more stable glycemic control. Starting from our previous highly potent compound with a thienoprimidine scaffold, which is unfortunately severely hit by hepatic biotransformation, a lead compound was rapidly generated by drawing on the experience of our previously discovered long-acting compounds with 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 have high potency, a fine pharmacokinetic profile, and a long-acting in vivo efficacy.
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