Discovery of novel 5‐methyl‐1 H ‐pyrazole derivatives as potential antiprostate cancer agents: Design, synthesis, molecular modeling, and biological evaluation

• Published in: Chemical biology & drug design Vol. 91; no. 6; pp. 1113 - 1124
• Main Authors: Zhang, Daoguang, Asnake, Solomon, Zhang, Jingya, Olsson, Per‐Erik, Zhao, Guisen
• Format: Journal Article
• Language: English
• Published: 01-06-2018
• ISSN: 1747-0277; 1747-0285
• DOI: 10.1111/cbdd.13173

Androgen receptor (
AR
) signaling functions as a core driving force for the progression of prostate cancer (
PC
a), 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‐1
H
‐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
PC
a
LNC
aP cells more efficiently than enzalutamide.
A13
and
A14
also showed improved metabolic stability compared with
10e
in human liver microsomes.