title: FK143, a novel nonsteroidal inhibitor of steroid 5 alpha-reductase: (1) In vitro effects on human and animal prostatic enzymes.
abstract: Steroid 5 alpha-reductase is an enzyme which converts testosterone into 5 alpha-dihydrotestosterone (DHT) and is implicated in the pathogenesis of benign prostatic hyperplasia (BPH) in men. We studied in vitro effects of FK143, a nonsteroidal new compound, on 5 alpha-reductase in human and animal prostates. Prostates were obtained from Wistar rats, Beagle dogs, and Cynomolgus monkeys as well as prostatic tissue from BPH patients obtained by the prostatectomy. Nuclear membrane fraction of prostates showed pH dependent 5 alpha-reductase activities, and inhibitory effects of drugs were assayed at pH 6.5. FK143 inhibited human prostatic 5 alpha-reductase in a dose-dependent manner with an IC50 of 1.9 nM and also inhibited animal 5 alpha-reductases with similar IC50 values. FK143 inhibited human and rat 5 alpha-reductases in a noncompetitive fashion while finasteride, a steroidal 5 alpha-reductase inhibitor, showed competitive inhibition. The affinities of FK143 for the human 5 alpha-reductase is constant at pH 5 and 6.5. No inhibitory effects were shown to other oxidoreductases. These results indicate that FK143 is a new type of potent and selective 5 alpha-reductase inhibitor.
authors.affiliation: Exploratory Research Laboratories, Fujisawa Pharmaceutical Co. Ltd, Tsukuba Japan.
authors.forename: J
authors.initials: J
authors.lastname: Hirosumi
authors.forename: O
authors.initials: O
authors.lastname: Nakayama
authors.forename: T
authors.initials: T
authors.lastname: Fagan
authors.forename: K
authors.initials: K
authors.lastname: Sawada
authors.forename: N
authors.initials: N
authors.lastname: Chida
authors.forename: M
authors.initials: M
authors.lastname: Inami
authors.forename: S
authors.initials: S
authors.lastname: Takahashi
authors.forename: H
authors.initials: H
authors.lastname: Kojo
authors.forename: Y
authors.initials: Y
authors.lastname: Notsu
authors.forename: M
authors.initials: M
authors.lastname: Okuhara
mesh_terms: D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase / Q000302:isolation & purification / Q000378:metabolism; D058891:5-alpha Reductase Inhibitors; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018120:Finasteride / Q000494:pharmacology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007211:Indoles / Q000494:pharmacology*; D008252:Macaca fascicularis; D008297:Male; D009685:Nuclear Envelope / Q000201:enzymology; D010654:Phenylbutyrates / Q000494:pharmacology*; D011467:Prostate / Q000201:enzymology*; D051381:Rats; D017208:Rats, Wistar; D013045:Species Specificity; D013739:Testosterone / Q000494:pharmacology
chemical_list: C093354:4-(3-(3-(bis(4-isobutylphenyl)methylamino)benzoyl)-1H-indol-1-yl)butyric acid; D058891:5-alpha Reductase Inhibitors; D007211:Indoles; D010654:Phenylbutyrates; D013739:Testosterone; D018120:Finasteride; D013741:3-Oxo-5-alpha-Steroid 4-Dehydrogenase