UNIQUE PRECLINICAL CHARACTERISTICS OF GG745, A POTENT DUAL INHIBITOR OF 5AR

Selective inhibition of type 2 5 alpha-reductase has been shown to be efficacious in the treatment of benign prostatic hyperplasia. Pharmaco kinetic and pharmacodynamic results are reported of treatment with a p otent inhibitor of both 5 alpha-reductase isozymes, GG745, in rats, do gs and men. In the rat, GG745 has a similar effect on DHT-driven prost atic growth as finasteride, another dual 5 alpha-reductase inhibitor i n this species. However, GG745 appears to be more potent in the rat, a result that likely reflects the greater inherent potency and terminal half-life of GG745 (14 hr) compared with that of finasteride (1 hr). These pharmacokinetic differences are also maintained in the dog (65 a nd 4 hr for GG745 and finasteride, respectively). From these results, the literature, and in vitro studies, we estimated doses of GG745 like ly to prove efficacious in reducing DHT levels in man. These estimated values were predictive of single-dose effects of GG745 in man. Result s from single-dose evaluations in man indicate that GG745 has a termin al half-life of similar to 240 hr, and single doses of >10 mg decrease d DHT levels significantly more than did single 5-mg doses of finaster ide, These data support the hypothesis that a molecule (GG745) that ef fectively inhibits both 5 alpha-reductases will lower serum DHT levels significantly more than a molecule that inhibits only a single 5 alph a-reductase isozyme (e.g., finasteride, a selective inhibitor of the t ype 2 enzyme in man).