BENZO[C]QUINOLIZIN-3-ONES: A NOVEL CLASS OF POTENT AND SELECTIVE NONSTEROIDAL INHIBITORS OF HUMAN STEROID 5?-REDUCTASE 1 (Articolo in rivista)

Type
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  • BENZO[C]QUINOLIZIN-3-ONES: A NOVEL CLASS OF POTENT AND SELECTIVE NONSTEROIDAL INHIBITORS OF HUMAN STEROID 5?-REDUCTASE 1 (Articolo in rivista) (literal)
Anno
  • 2000-01-01T00:00:00+01:00 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#doi
  • 10.1021/jm000945r (literal)
Alternative label
  • Guarna, Antonio; Machetti, Fabrizio; Occhiato, Ernesto Giovanni; Scarpi, Dina; Comerci, A.; Danza, Giovanna; Mancina, Rosa; Serio, Mario; Hardy, K. (2000)
    BENZO[C]QUINOLIZIN-3-ONES: A NOVEL CLASS OF POTENT AND SELECTIVE NONSTEROIDAL INHIBITORS OF HUMAN STEROID 5?-REDUCTASE 1
    in Journal of medicinal chemistry; American Chemical Society, Washington (Stati Uniti d'America)
    (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#autori
  • Guarna, Antonio; Machetti, Fabrizio; Occhiato, Ernesto Giovanni; Scarpi, Dina; Comerci, A.; Danza, Giovanna; Mancina, Rosa; Serio, Mario; Hardy, K. (literal)
Pagina inizio
  • 3718 (literal)
Pagina fine
  • 3735 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroVolume
  • 43 (literal)
Rivista
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#pagineTotali
  • 18 (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#numeroFascicolo
  • 20 (literal)
Note
  • Scopu (literal)
  • PubMe (literal)
  • ISI Web of Science (WOS) (literal)
Http://www.cnr.it/ontology/cnr/pubblicazioni.owl#affiliazioni
  • Centro di studio della chimica e della struttura dei composti eterociclici del CNR, Dipartimento di chimica Organica 'Ugo Schiff' dell'Università di Firenze Dipartimento di fisiopatologia unità di endocrinologia dell'Università di Firenze Ares Serono Int, Serono Pharmaceut Res Inst, CH-1211 Geneva, Switzerland (literal)
Titolo
  • BENZO[C]QUINOLIZIN-3-ONES: A NOVEL CLASS OF POTENT AND SELECTIVE NONSTEROIDAL INHIBITORS OF HUMAN STEROID 5?-REDUCTASE 1 (literal)
Abstract
  • The synthesis and biological evaluation of a series of novel, selective inhibitors of isoenzyme 1 of human 5 alpha-reductase (5 alpha R) (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 5 alpha R-1 and 5 alpha R-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 las 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 5 alpha R-1 expressed in CHO cells, were also tested toward native 5 alpha R-1 in human scalp and 5 alpha R-2 in human prostate homogenates, in comparison with finasteride and the known 5 alpha R-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 5 alpha R-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 (literal)
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