Pyrazol-1-yl-propanamides as SARD and Pan-Antagonists for the Treatment of Enzalutamide-Resistant Prostate Cancer

We report herein the design, synthesis,
and pharmacological characterization of a library of novel aryl pyrazol-1-yl-propanamides
as selective androgen receptor degraders (SARDs) and pan-antagonists
that exert broad-scope AR antagonism. Pharmacological evaluation demonstrated
that introducing a pyrazole moiety as the B-ring structural element
in the common A-ring–linkage–B-ring nonsteroidal antiandrogens’
general pharmacophore allowed the development of a new scaffold of
small molecules with unique SARD and pan-antagonist activities even
compared to our recently published AF-1 binding SARDs such as UT-155
(9) and UT-34 (10). Novel B-ring pyrazoles
exhibited potent AR antagonist activities, including promising distribution,
metabolism, and pharmacokinetic properties, and broad-spectrum AR
antagonist properties, including potent in vivo antitumor
activity. 26a was able to induce an 80% tumor growth
inhibition of xenografts derived from the enzalutamide-resistant (Enz-R)
VCaP cell line. These results represent an advancement toward the
development of novel AR antagonists for the treatment of Enz-R prostate
cancer.