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Premium Discovery of an Orally Active and Long‐Acting DPP‐IV Inhibitor through Property‐Based Optimization with an in Silico Biotransformation Prediction Tool
Author(s)
Zeng Shaogao,
Dou Wenyuan,
Li Manna,
Zhou Yang,
Guo Jiehuang,
Zhao Nan,
Huang Hong,
Zhou Qiaoli,
Hu Wenhui,
Ma Yanfang,
Zhao Xin,
Xie Hui
Publication year2020
Publication title
chemmedchem
Resource typeJournals
PublisherWiley
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.
Subject(s)biochemistry , biology , biotransformation , chemistry , computational biology , dipeptidyl peptidase , drug discovery , enzyme , gene , in silico , in vitro , in vivo , lead compound , microbiology and biotechnology , pharmacokinetics , pharmacology , stereochemistry
Language(s)English
SCImago Journal Rank0.817
H-Index100
eISSN1860-7187
pISSN1860-7179
DOI10.1002/cmdc.202000175

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