title: Benzo[c]quinolizin-3-ones: a novel class of potent and selective nonsteroidal inhibitors of human steroid 5alpha-reductase 1.
abstract: The synthesis and biological evaluation of a series of novel, selective inhibitors of isoenzyme 1 of human 5alpha-reductase (5alphaR) (EC 1.3.99.5) are reported. The inhibitors are 4aH- (19-29) or 1H-tetrahydrobenzo[c]quinolizin-3-ones (35-47) bearing at positions 1, 4, 5, and 6 a methyl group and at position 8 a hydrogen, methyl group, or chlorine atom. All these compounds were tested toward 5alphaR-1 and 5alphaR-2 expressed in CHO cells (CHO 1827 and CHO 1829, respectively) resulting in selective inhibitors of the type 1 isoenzyme, with inhibitory potencies (IC(50)) ranging from 7.6 to 9100 nM. The inhibitors of the 4aH-series, having a double bond at position 1,2, were generally less active than the corresponding inhibitors of the 1H-series having the double bond at position 4,4a on the A ring. The presence of a methyl group at position 4 (as in compounds 39-40 and 45-47), associated with a substituent at position 8, determined the highest inhibition potency (IC(50) from 7.6 to 20 nM). Compounds 39 and 40, having K(i) values of 5.8+/-1.8 and 2.7+/-0.6 nM, respectively, toward 5alphaR-1 expressed in CHO cells, were also tested toward native 5alphaR-1 in human scalp and 5alphaR-2 in human prostate homogenates, in comparison with finasteride and the known 5alphaR-1-selective inhibitor LY191704, and their mechanism of inhibition was determined. They both inhibited the enzyme through a reversible competitive mechanism and again were selective inhibitors of 5alphaR-1 with IC(50) values of 41 nM. These specific features make these inhibitors suitable candidates for further development as drugs in the treatment of DHT-dependent disorders such as acne and androgenic alopecia in men and hirsutism in women.
authors.affiliation: Departimento di Chimica Organica "U. Schiff" and Centro di Studio sullaChimica e la Struttura dei Composti Eterociclici e loro Applicazioni, Università di Firenze, Italy. guarna@chimorg.unifi.it
authors.forename: A
authors.initials: A
authors.lastname: Guarna
authors.forename: F
authors.initials: F
authors.lastname: Machetti
authors.forename: E G
authors.initials: EG
authors.lastname: Occhiato
authors.forename: D
authors.initials: D
authors.lastname: Scarpi
authors.forename: A
authors.initials: A
authors.lastname: Comerci
authors.forename: G
authors.initials: G
authors.lastname: Danza
authors.forename: R
authors.initials: R
authors.lastname: Mancina
authors.forename: M
authors.initials: M
authors.lastname: Serio
authors.forename: K
authors.initials: K
authors.lastname: Hardy
mesh_terms: D058891:5-alpha Reductase Inhibitors; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors; D008297:Male; D008958:Models, Molecular; D008968:Molecular Conformation; D009010:Monte Carlo Method; D011467:Prostate / Q000378:metabolism; D011807:Quinolizines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D012535:Scalp / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: C415160:2,3,5,6-tetrahydro-4,8-dimethylbenzo(c)quinolizin-3-one; D058891:5-alpha Reductase Inhibitors; C415161:8-chloro-2,3,5,6-tetrahydro-4-methylbenzo(c)quinolizin-3-one; D004791:Enzyme Inhibitors; D007527:Isoenzymes; D011807:Quinolizines; D011994:Recombinant Proteins