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 year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.202000175
Subject(s) - in silico , biotransformation , chemistry , drug discovery , pharmacology , in vivo , pharmacokinetics , lead compound , dipeptidyl peptidase , stereochemistry , computational biology , biochemistry , enzyme , in vitro , biology , microbiology and biotechnology , gene
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.