title: Discovery of orteronel (TAK-700), a naphthylmethylimidazole derivative, as a highly selective 17,20-lyase inhibitor with potential utility in the treatment of prostate cancer.
abstract: A novel naphthylmethylimidazole derivative 1 and its related compounds were identified as 17,20-lyase inhibitors. Based on the structure-activity relationship around the naphthalene scaffold and the results of a docking study of 1a in the homology model of 17,20-lyase, the 6,7-dihydro-5H-pyrrolo[1,2-c]imidazole derivative (+)-3c was synthesized and identified as a potent and highly selective 17,20-lyase inhibitor. Biological evaluation of (+)-3c at a dose of 1mg/kg in a male monkey model revealed marked reductions in both serum testosterone and dehydroepiandrosterone concentrations. Therefore, (+)-3c (termed orteronel [TAK-700]) was selected as a candidate for clinical evaluation and is currently in phase III clinical trials for the treatment of castration-resistant prostate cancer.
authors: CNS Drug Discovery Unit, Takeda Pharmaceutical Company, Ltd., Shonan Research Center, 26-1, Muraoka-Higashi 2-Chome, Fujisawa, Kanagawa 251-0012, Japan. Kaku_Tomohiro@takeda.co.jp
authors: Tomohiro
authors: T
authors: Kaku
authors: Takenori
authors: T
authors: Hitaka
authors: Akio
authors: A
authors: Ojida
authors: Nobuyuki
authors: N
authors: Matsunaga
authors: Mari
authors: M
authors: Adachi
authors: Toshimasa
authors: T
authors: Tanaka
authors: Takahito
authors: T
authors: Hara
authors: Masuo
authors: M
authors: Yamaoka
authors: Masami
authors: M
authors: Kusaka
authors: Teruaki
authors: T
authors: Okuda
authors: Satoru
authors: S
authors: Asahi
authors: Shuichi
authors: S
authors: Furuya
authors: Akihiro
authors: A
authors: Tasaka
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D018360:Crystallography, X-Ray; D003687:Dehydroepiandrosterone / Q000097:blood; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000882:Haplorhini; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009281:Naphthalenes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology; D013237:Stereoisomerism; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013739:Testosterone / Q000097:blood
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007093:Imidazoles; D009281:Naphthalenes; D013739:Testosterone; D003687:Dehydroepiandrosterone; D013254:Steroid 17-alpha-Hydroxylase