LY191704: A Selective, Nonsteroidal Inhibitor of Human Steroid 5α- Reductase Type 1

Androgens, in particular dihydrotestosterone (DHT), play a key role in differentiation, growth, and maintenance of the mammalian prostate. Production of DHT from testosterone is catalyzed by two distinct membrane-bound steroid 5α-reductase [5α-reductase; 3-oxo-5α-steroid Δ4-dehydrogenase; 3-oxo-5α-steroid:(acceptor) Δ4-oxidoreductase, EC 1.3.99.5] isozymes designated types 1 and 2. Benign prostatic hyperplasia (BPH), a disease that occurs almost universally in males, is characterized by obstructive and irritative urinary voiding symptoms and has been associated with an overproduction of DHT. Recently, steroidal inhibitors of 5α-reductase type 2 have been used successfully for treatment of BPH. Described here is a nonsteroidal inhibitor of 5α-reductase type 1, LY191704 {8-chloro-4-methyl-1,2,3,4,4a,5,6,10b-octaahydro-benzo [f]quinolin-3(2H)-one}. This compound was identified based on its capacity to inhibit 5α-reductase activity in a human genital skin fibroblast cell line (Hs68). Surprisingly, LY191704 is inactive when tested in freshly isolated prostate cells obtained from subjects with BPH, whereas previously described 4-azasteroids are active. LY191704 is, however, a potent inhibitor of the 5α-reductase activity of BPH cells that have been maintained in culture. Analysis of human and rat 5α-reductases expressed from transfected cDNAs in simian COS cells indicates that LY191704 is a specific noncompetitive inhibitor of the human 5α-reductase type 1. Taken together, the results suggest that prostate cells have the capacity to express both 5α-reductase isozymes and that LY191704 may be useful in treatment of human endocrine disorders associated with overproduction of DHT by 5α-reductase type 1.