FK143, a novel nonsteroidal inhibitor of steroid 5α-reductase: (1) In vitro effects on human and animal prostatic enzymes

doi:10.1016/0960-0760(94)00187-Q

The Journal of Steroid Biochemistry and Molecular Biology

Volume 52, Issue 4, April 1995, Pages 357-363

https://doi.org/10.1016/0960-0760(94)00187-Q Get rights and content

Abstract

Steroid 5α-reductase is an enzyme which converts testosterone into 5α-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 5α-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 5α-reductase activities, and inhibitory effects of drugs were assayed at pH 6.5. FK143 inhibited human prostatic 5α-reductase in a dose-dependent manner with an IC₅₀ of 1.9nM and also inhibited animal 5α-reductases with similar IC₅₀ values. FK143 inhibited human and rat 5α-reductases in a noncompetitive fashion while finasteride, a steroidal 5α-reductase inhibitor, showed competitive inhibition. The affinities of FK143 for the human 5α-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 5α-reductase inhibitor.

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PaperFK143, a novel nonsteroidal inhibitor of steroid 5α-reductase: (1) In vitro effects on human and animal prostatic enzymes

Abstract

J. Biol. Chem.

Trends Pharmacol. Sci.

Am. J. Med.

J. Urol.

Steroids

J. Steroid Biochem. Molec. Biol.

J. Steroid Biochem.

Selective retention of dihydrotestosterone by prostatic nuclei

Nature

Biological actions of androgens

Endocrine. Rev.

Characterization of the cytosol androgen receptor of the human prostate

J. Clin. Endocrinol. Metab.

Benign prostatic hyperplasia: pathogenesis and medical therapy

J. Am. Geriatr. Soc.

Steroid 5α-reductase deficiency in man: an inherited form of male pseudohermaphroditism

Science

Steroid 5α-reductase deficiency in a 65-year-old male pseudohermaphrodite: the natural history, ultrastructure of the testes, and evidence for inherited enzyme heterogeneity

J. Clin. Endocrinol. Metab.

Azasteroids as inhibitors of rat prostatic 5α-reductase

J. Med. Chem.

The effect of finasteride in men with benign prostatic hyperplasia

New Engl. J. Med.

Paper
FK143, a novel nonsteroidal inhibitor of steroid 5α-reductase: (1) In vitro effects on human and animal prostatic enzymes