title: Unique preclinical characteristics of GG745, a potent dual inhibitor of 5AR.
abstract: Selective inhibition of type 2 5alpha-reductase has been shown to be efficacious in the treatment of benign prostatic hyperplasia. Pharmacokinetic and pharmacodynamic results are reported of treatment with a potent inhibitor of both 5alpha-reductase isozymes, GG745, in rats, dogs and men. In the rat, GG745 has a similar effect on DHT-driven prostatic growth as finasteride, another dual 5alpha-reductase inhibitor in 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 and 4 hr for GG745 and finasteride, respectively). From these results, the literature, and in vitro studies, we estimated doses of GG745 likely to prove efficacious in reducing DHT levels in man. These estimated values were predictive of single-dose effects of GG745 in man. Results from single-dose evaluations in man indicate that GG745 has a terminal half-life of approximately 240 hr, and single doses of >10 mg decreased DHT levels significantly more than did single 5-mg doses of finasteride. These data support the hypothesis that a molecule (GG745) that effectively inhibits both 5alpha-reductases will lower serum DHT levels significantly more than a molecule that inhibits only a single 5alpha-reductase isozyme (e.g., finasteride, a selective inhibitor of the type 2 enzyme in man).
authors.affiliation: Division of Biochemistry, Glaxo Wellcome Research Institute, Research Triangle Park, North Carolina 27709, USA.
authors.forename: H N
authors.initials: HN
authors.lastname: Bramson
authors.forename: D
authors.initials: D
authors.lastname: Hermann
authors.forename: K W
authors.initials: KW
authors.lastname: Batchelor
authors.forename: F W
authors.initials: FW
authors.lastname: Lee
authors.forename: M K
authors.initials: MK
authors.lastname: James
authors.forename: S V
authors.initials: SV
authors.lastname: Frye
mesh_terms: D000818:Animals; D001378:Azasteroids / Q000493:pharmacokinetics / Q000494:pharmacology*; D042944:Cholestenone 5 alpha-Reductase; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D000068538:Dutasteride; D004791:Enzyme Inhibitors / Q000493:pharmacokinetics / Q000494:pharmacology*; D018120:Finasteride / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D008297:Male; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar
chemical_list: D001378:Azasteroids; D004791:Enzyme Inhibitors; D018120:Finasteride; D010088:Oxidoreductases; D042944:Cholestenone 5 alpha-Reductase; D000068538:Dutasteride