Synthesis and pharmacological evaluation of novel arylpiperazine derivatives as nonsteroidal androgen receptor antagonists.
The search for novel antiandrogens by high-throughput screening (HTS) of the Yamanouchi chemical library led to the discovery of the lead compound (5), which possesses an arylmorpholine moiety. Through the optimization of the lead compound (5), we have found a series of novel arylpiperazine derivatives. Among them, 4-[4-cyano-(3-trifluoromethyl)phenyl]-N-(4-fluorophenyl)piperazine-1-carboxamide (22; YM-92088) exhibited a potent AR antagonistic activity with an IC(50) value of 0.47 microM in the reporter assay, which is more potent than bicalutamide (4) which has an IC(50) value of 0.89 microM.
Kinoyama
Isao
I
Institute for Drug Discovery Research, Yamanouchi Pharmaceutical Co. Ltd., 21 Miyukigaoka, Tsukuba, Ibaraki 305-8585, Japan. kinoyama@yamanouchi.co.jp
Taniguchi
Nobuaki
N
Yoden
Toru
T
Koutoku
Hiroshi
H
Furutani
Takashi
T
Kudoh
Masafumi
M
Okada
Minoru
M
D059002:Androgen Receptor Antagonists; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D011944:Receptors, Androgen / Q000096:biosynthesis
D059002:Androgen Receptor Antagonists; D010879:Piperazines; D011944:Receptors, Androgen