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Novel Pyrimidines as Multitarget Protein Tyrosine Kinase Inhibitors for the Treatment of Idiopathic Pulmonary Fibrosis (IPF)
Author(s) -
Sun Bo,
Liu Xiaowen,
Zheng Xu,
Wang Changyuan,
Meng Qiang,
Sun Huijun,
Shu Xiaohong,
Liu Kexin,
Sun Xiuli,
Li Yanxia,
Ma Xiaodong
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.201900606
Subject(s) - tyrosine kinase , idiopathic pulmonary fibrosis , chemistry , kinase , pyrimidine , in vivo , pharmacology , tyrosine kinase inhibitor , acrylamide , tyrosine , enzyme , cancer research , biochemistry , medicine , biology , signal transduction , cancer , lung , microbiology and biotechnology , organic chemistry , copolymer , polymer
A new class of pyrimidine derivatives were identified as potent protein tyrosine kinase (PTK) inhibitors for the treatment of idiopathic pulmonary fibrosis (IPF). Most of these small‐molecule inhibitors displayed strong enzymatic activity against BTK and JAK3 kinases at concentrations lower than 10 nM. The representative compound N ‐(3‐((5‐chloro‐2‐(4‐((1‐morpholino)acetylamino)phenylamino)‐4‐pyrimidinyl)amino)phenyl)acrylamide ( 6 a ) also exhibited high inhibitory potency toward both BTK and JAK kinase families, as well as ErbB4, at a concentration of 10 nM, achieving rates of inhibition higher than 57 %. Additionally, in vivo biological evaluations showed that 6 a can remarkably decrease the severity of IPF disease. All these investigations suggested that the multi‐PTK inhibitor 6 a may serve as a promising agent for the treatment of IPF.