Benzo[c]quinolizin-3-ones: a novel class of potent and selective nonsteroidal inhibitors of human steroid 5alpha-reductase 1.

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Guarna A, Machetti F, Occhiato EG, Scarpi D, Comerci A, Danza G, Mancina R, Serio M, Hardy K

Benzo[c]quinolizin-3-ones: a novel class of potent and selective nonsteroidal inhibitors of human steroid 5alpha-reductase 1.

J Med Chem. 2000 Oct 5;43(20):3718-35.

PubMed ID

11020287 [ View in PubMed

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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.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Finasteride	3-oxo-5-alpha-steroid 4-dehydrogenase 1	Ki (nM)	366	N/A	N/A	Details
Finasteride	3-oxo-5-alpha-steroid 4-dehydrogenase 2	IC 50 (nM)	2.2	N/A	N/A	Details