LY191704 - A SELECTIVE, NONSTEROIDAL INHIBITOR OF HUMAN STEROID 5-ALPHA-REDUCTASE TYPE-1

Androgens, in particular dihydrotestosterone (DHT), play a key role in differentiation, growth, and maintenance of the mammalian prostate. P roduction of DHT from testosterone is catalyzed by two distinct membra ne-bound steroid 5alpha-reductase [5alpha-reductase; 3-oxo-5alpha-ster oid DELTA4-dehydrogenase; 3-oxo-5alpha-steroid:(acceptor) DELTA4-oxido reductase, EC 1.3.99.5] isozymes designated types 1 and 2. Benign pros tatic hyperplasia (BPH), a disease that occurs almost universally in m ales, is characterized by obstructive and irritative urinary voiding s ymptoms and has been associated with an overproduction of DHT. Recentl y, steroidal inhibitors of 5alpha-reductase type 2 have been used succ essfully for treatment of BPH. Described here is a nonsteroidal inhibi tor of 5alpha-reductase type 1, LY191704 4a,5,6,10b-octaahydro-benzo[f ]quinolin-3(2H)-one}. This compound was identified based on its capaci ty to inhibit 5alpha-reductase activity in a human genital skin fibrob last cell line (Hs68). Surprisingly, LY191704 is inactive when tested in freshly isolated prostate cells obtained from subjects with BPH, wh ereas previously described 4-azasteroids are active. LY191704 is, howe ver, a potent inhibitor of the 5alpha-reductase activity of BPH cells that have been maintained in culture. Analysis of human and rat 5alpha -reductases expressed from transfected cDNAs in simian COS cells indic ates that LY191704 is a specific noncompetitive inhibitor of the human 5alpha-reductase type 1. Taken together, the results suggest that pro state cells have the capacity to express both 5alpha-reductase isozyme s and that LY191704 may be useful in treatment of human endocrine diso rders associated with overproduction of DHT by 5alpha-reductase type 1 .