Pharmacokinetics-Driven Optimization of 7-Methylimidazo[1,5- a]pyrazin-8(7H)-one as Novel BRD4 Inhibitors

Yifei Yang; Pan Chen; Leilei Zhao; Fangqing Zhang; Huibin Zhang; Jinpei Zhou

doi:10.1021/acsmedchemlett.9b00474

Pharmacokinetics-Driven Optimization of 7-Methylimidazo[1,5- a]pyrazin-8(7H)-one as Novel BRD4 Inhibitors

ACS Med Chem Lett. 2019 Nov 26;10(12):1680-1685. doi: 10.1021/acsmedchemlett.9b00474. eCollection 2019 Dec 12.

Authors

Yifei Yang^{1

2}, Pan Chen¹, Leilei Zhao³, Fangqing Zhang³, Huibin Zhang³, Jinpei Zhou¹

Affiliations

¹ Department of Medicinal Chemistry, China Pharmaceutical University, Nanjing 210009, PR China.
² Department of Pharmaceutical Sciences, College of Pharmacy, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, United States.
³ Center of Drug Discovery, Jiangsu Key Laboratory of Drug Discovery for Metabolic Disease, China Pharmaceutical University, Nanjing 210009, PR China.

Abstract

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 (IC₅₀ = 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.