Open AccessPharmacokinetics-Driven Optimization of 7-Methylimidazo[1,5-a]pyrazin-8(7H)-one as Novel BRD4 Inhibitors
Author(s) -
Yifei Yang,
Pan Chen,
Leilei Zhao,
Fangqing Zhang,
Huibin Zhang,
Jinpei Zhou
Publication year - 2019
Publication title -
acs medicinal chemistry letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.065
H-Index - 66
ISSN - 1948-5875
DOI - 10.1021/acsmedchemlett.9b00474
Subject(s) - potency , microsome , bromodomain , brd4 , chemistry , in vitro , ic50 , substituent , pharmacokinetics , pharmacology , cancer research , biochemistry , stereochemistry , medicine , dna , histone
The BET bromodomain containing protein (BRD4) plays a key role in transcription regulation. Therefore, efforts to generate BRD4 inhibitors with excellent potency and DMPK properties are of clinical value. As a continuing work to improve the stability in in vitro metabolic experiments of liver microsomes of our previously reported 7-methylimidazo[1,5- a ]pyrazin-8(7H)-one, our optimization of this poor pharmacokinetics focusing on the phenyl substituent is performed. Fortunately, compound 17 displayed subnanomolar potency (IC 50 = 30 nM ) against BRD4(1), and its liver microsome stability in human, rat, and mouse are more favorable than previously reported inhibitor 28 . Compound 17 exhibited antitumor efficacy with no significant toxicity in xenograft models of pancreatic cancer. In addition, fluorescent probe and nuclei-specific dye were utilized to verify apoptosis-inducing of compound 17 via intranuclear potency in BXPC-3 cell line.