Discovery of novel 5-methyl-1H-pyrazole derivatives as potential anti-prostate cancer agents: design, synthesis, molecular modeling and biological evaluation

Abstract

Androgen receptor (AR) signaling functions as a core driving force for the progression of prostate cancer (PCa), and AR has been proved to be an effective therapeutic target even for castration resistant prostate cancer (CRPC). Herein, structural modification via a fragments splicing strategy was performed based on two lead compounds T3 and 10e, leading to the discovery of a series of 5-methyl-1H-pyrazole derivatives. AR reporter gene assay revealed compounds A13 and A14 as potent AR antagonists. Some of the compounds in this series inhibited growth of PCa LNCaP cells more efficiently than enzalutamide. A13 and A14 also showed improved metabolic stability comparing with 10e in human liver microsomes.

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Structure optimization via a fragments splicing strategy led to the discovery of a series of 5-methyl-1H-pyrazole derivatives. Part of the compounds showed strong growth inhibition in prostate cancer LNCap cells. AR luciferase reporter gene assay revealed compounds A13 and A14 as potent AR antagonists.

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