title: CGP 53153: a new potent inhibitor of 5alpha-reductase.
abstract: CGP 53153 (N-2-(cyano-2-propyl)-3-oxo-4-aza-5alpha-androst-1-ene-17beta-carb oxamide) is a steroidal inhibitor of 5alpha-reductase, the enzyme which effects the conversion of testosterone (T) to 5alpha-dihydrotestosterone (DHT). In vitro, CGP 53153 competitively inhibited rat microsomal 5alpha-reductase from prostate by 50% (IC50) at a concentration of 36nM compared to the reference compound finasteride which inhibited 5alpha-reductase with an IC50 of 11 nM in the same system. In vivo, inhibition of 5alpha-reductase activity was characterized in three different test systems. Inhibition of 5alpha-reductase activity was first assessed in a standard test designed to compare directly the potency of different 5alpha-reductase inhibitors. This test assesses potency through the inhibition of prostate growth in juvenile castrate male rats treated with a standard dose of T-propionate (1 mg/kg, s.c.) and a 5alpha-reductase inhibitor administered orally at various doses for 4 days. CGP 53153 and finasteride significantly reduced T-propionate-mediated prostate growth by about 25% (ED25) compared to T-propionate-treated controls at oral doses of 0.01 and 0.1 mg/kg, respectively. Second, the effects on prostate weight were studied in normal adult male rats treated orally once daily for 14 days with 1, 3 and 10 mg/kg CGP 53153 and with 10 mg/kg finasteride. CGP 53153 significantly reduced prostate weight at 3 and 10 mg/kg by 31% and 37%, respectively, compared to vehicle-treated controls, whereas the dose of 10 mg/kg finasteride did not significantly reduce prostate weight. Third, the effects on prostate volume were studied in normal 6-9-year-old male dogs treated orally once daily with 5 mg/kg CGP 53153 and with 5 mg/kg finasteride for 12 weeks. Prostate volume was monitored with magnetic resonance imaging every 2 weeks beginning 6 weeks before start of the treatment with 5alpha-reductase inhibitors and ending after a recovery period of 8 weeks after termination of treatment. Treatment for 12 weeks with both CGP 53153 and finasteride was equally effective in reducing prostate volume by more than 70% in individual dogs. Anti-androgenic potency of CGP 53153 and finasteride was assessed in juvenile castrate male rats treated with DHT-propionate (1 mg/kg, s.c.) and a 5alpha-reductase inhibitor (p.o.) for 4 days. Neither CGP 53153 nor finasteride given at a dose of 10 mg/kg had any significant effect on DHT-propionate-mediated prostate growth, whereas the reference anti-androgen flutamide given at a dose of 10 mg/kg reduced prostate weight to levels comparable to those seen in untreated castrate animals. For CGP 53153, the dose of 10 mg/kg is 1000-fold higher than the ED25 for 5alpha-reductase inhibition in vivo. In conclusion, both CGP 53153 and finasteride are potent inhibitors of the rat 5alpha-reductase enzyme system in vitro without showing any anti-androgenic effects in vivo. Both CGP 53153 and finasteride were equally potent in reducing prostate volume in aged male dogs, whereas in rats, CGP 53153 is up to 10 times more potent than finasteride in reducing prostate weight as shown in two different rat models.
authors.affiliation: Research Department, Pharmaceuticals Division, CIBA-GEIGY Ltd, Basel, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Häusler
authors.forename: P R
authors.initials: PR
authors.lastname: Allegrini
authors.forename: M
authors.initials: M
authors.lastname: Biollaz
authors.forename: C
authors.initials: C
authors.lastname: Batzl
authors.forename: E
authors.initials: E
authors.lastname: Scheidegger
authors.forename: A S
authors.initials: AS
authors.lastname: Bhatnagar
mesh_terms: D058891:5-alpha Reductase Inhibitors; D000818:Animals; D001835:Body Weight / Q000187:drug effects; D013196:Dihydrotestosterone / Q000494:pharmacology; D004285:Dogs; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018120:Finasteride / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008861:Microsomes / Q000201:enzymology; D009919:Orchiectomy; D009929:Organ Size / Q000187:drug effects; D011467:Prostate / Q000201:enzymology / Q000254:growth & development; D051381:Rats
chemical_list: D058891:5-alpha Reductase Inhibitors; C099761:CGP 53153; D004791:Enzyme Inhibitors; D013196:Dihydrotestosterone; D018120:Finasteride