Σπύρος
Μέλος του προσωπικού
Το FK143 είναι ένα νέο μη στεροειδές αντιανδρογόννο, το οποίο φαίνεται να είναι πιθανός μπλοκέρ της 5-alpha-reductase ουσίας απαραίτητης για την σύνθεση dht.
1. FK143, a novel nonsteroidal inhibitor of steroid 5 alpha-reductase: (1) In vitro effects on human and animal prostatic enzymes.
Author
Hirosumi J; Nakayama O; Fagan T; Sawada K; Chida N; Inami M; Takahashi S; Kojo H; Notsu Y; Okuhara M
Address
Exploratory Research Laboratories, Fujisawa Pharmaceutical Co. Ltd, Tsukuba Japan.
Source
J Steroid Biochem Mol Biol, 1995 Apr, 52:4, 357-63
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.
2. Novel steroid 5 alpha-reductase inhibitor FK143: its dual inhibition against the two isozymes and its effect on transcription of the isozyme genes.
Author
Kojo H; Nakayama O; Hirosumi J; Chida N; Notsu Y; Okuhara M
Address
Exploratory Research Laboratory, Fujisawa Pharmaceutical Co., Ltd, Tsukuba, Japan.
Source
Mol Pharmacol, 1995 Sep, 48:3, 401-6
Abstract
Recent cloning of the cDNAs for the two isozymes of steroid 5 alpha-reductase (EC 1.3.99.5) allowed individual expression of the isozymes and permitted us to investigate the action of steroid 5 alpha-reductase inhibitors against the individual isozymes without any ambiguity that may be caused by coexistence of the isozymes in tissue preparations. We examined the kinetic characteristics of FK143 (4-[3-[3-[bis(4-isobutylphenyl)methylamino]benzoyl]-1H -indol-1- yl]butyric acid), a novel nonsteroidal steroid 5 alpha-reductase inhibitor against cloned human and rat steroid 5 alpha-reductase isozymes. FK143 was shown to inhibit both isozymes equally. The mode of the inhibition of FK143 against both isozymes was noncompetitive. The inhibition constants Kie and Kies of FK143 for human types 1 and 2 were 27.0 and 19.6 nM and 19.9 and 14.5 nM, respectively. Species selectivity between human and rat of the inhibitory activity of FK143 against both isozymes was not found. We also examined the effect of FK143 on the in vivo expression of the genes encoding for the rat steroid 5 alpha-reductase isozymes. FK143 reduced the testosterone-induced increase in the amount of the type 1 mRNA in castrated rat, whereas it did not substantially affect the amount of the type 2 mRNA.