title: Design, synthesis, and biological evaluation of 4-arylmethyl-1-phenylpyrazole and 4-aryloxy-1-phenylpyrazole derivatives as novel androgen receptor antagonists.
abstract: A series of 4-arylmethyl-1-phenylpyrazole and 4-aryloxy-1-phenylpyrazole compounds B were designed, synthesized, and evaluated for their potential as new-generation androgen receptor (AR) antagonists therapeutically effective against castration-resistant prostate cancer (CRPC). Introduction of a bulky amide substituent (R(2)) to the terminal aryl ring of the 4-arylmethyl group favored the reduction of agonistic activity and improved the pharmacokinetic (PK) properties. Similarly, introduction of a bulky substituent in the 4-aryloxy derivatives also resulted in improved PK properties. Compounds 28 h and 44b exhibited potent antitumor effects against a CRPC model of LNCaP-hr cell line in a mouse xenograft model. On the contrary, bicalutamide showed only partial suppression of tumor growth. These results suggest that the novel pyrazole derivatives are new-generation AR antagonists, different from the 'first-generation' antagonists such as bicalutamide in a CRPC treatment model.
authors.affiliation: Pharmaceutical Research Division, Takeda Pharmaceutical Company Ltd, 26-1, Muraokahigashi 2-chome, Fujisawa, Kanagawa 251-8555, Japan. yamamoto_satoshi@takeda.co.jp
authors.forename: Satoshi
authors.initials: S
authors.lastname: Yamamoto
authors.forename: Naoki
authors.initials: N
authors.lastname: Tomita
authors.forename: Yuri
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Tomohiko
authors.initials: T
authors.lastname: Suzaki
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Kaku
authors.forename: Takahito
authors.initials: T
authors.lastname: Hara
authors.forename: Masuo
authors.initials: M
authors.lastname: Yamaoka
authors.forename: Naoyuki
authors.initials: N
authors.lastname: Kanzaki
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hasuoka
authors.forename: Atsuo
authors.initials: A
authors.lastname: Baba
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Ito
mesh_terms: D000284:Administration, Oral; D059002:Androgen Receptor Antagonists / Q000138:chemical synthesis* / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D015195:Drug Design; D006801:Humans; D008297:Male; D051379:Mice; D008819:Mice, Nude; D017430:Prostate-Specific Antigen / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology / Q000627:therapeutic use; D011725:Pyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D011944:Receptors, Androgen / Q000737:chemistry* / Q000378:metabolism; D014183:Transplantation, Heterologous
chemical_list: D059002:Androgen Receptor Antagonists; C573389:N-(6-((1-(3-chloro-4-cyanophenyl)-3,5-dimethyl-1H-pyrazol-4-yl)oxy)pyridin-3-yl)-2,2-dimethylpropanamide; D011720:Pyrazoles; D011725:Pyridines; D011944:Receptors, Androgen; C031280:pyrazole; D017430:Prostate-Specific Antigen