FK143, A NOVEL NONSTEROIDAL INHIBITOR OF STEROID 5-REDUCTASE .1. IN-VITRO EFFECTS ON HUMAN AND ANIMAL PROSTATIC ENZYMES

Steroid 5 alpha-reductase is an enzyme which converts testosterone int o 5 alpha-dihydrotestosterone (DHT) and is implicated in the pathogene sis 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 inh ibitory effects of drugs were assayed at pH 6.5. FK143 inhibited human prostatic 5 alpha-reductase in a dose-dependent manner with an IC50 o f 1.9nM and also inhibited animal 5 alpha-reductases with similar IC50 values. FK143 inhibited human and rat 5 alpha-reductases in a noncomp etitive fashion while finasteride, a steroidal 5 alpha-reductase inhib itor, showed competitive inhibition. The affinities of FK143 for the h uman 5 alpha-reductase is constant at pH5 and 6.5. No inhibitory effec ts were shown to other oxidoreductases. These results indicate that FK 143 is a new type of potent and selective 5 alpha-reductase inhibitor.