57361-81-6

The in vitro antiandrogenic activity of four new progesterone derivatives: 4, 5, 6 and 7 (8 is a known compound) was determined. These compounds were evaluated as 5α-reductase inhibitors as well as by their capacity to bind to the androgen receptor in gonadectomized hamster prostate. The IC50 value was determined using increasing concentrations of 4, 5, 6, 7 and 8 in the presence of [3H]T and the microsomal fraction of the hamster prostate containing the 5α-reductase enzyme. In this paper we also demonstrated the effect of increasing concentrations of the novel steroids upon [3H]DHT binding to the androgen receptors from hamster prostate which produces competition for the androgen receptor sites. The in vitro studies showed that steroids 4, 5, 6, 7 and 8 had an inhibitory activity for the 5α-reductase with IC50 of: 4 (0.17 μM), 5 (0.19 μM), 6 (1 μM), 7 (4.2 μM), and 8 (2.7 μM). On the other hand, the IC 50 value for compounds 4, 5, 6, 7, 8 and DHT showed the following order of affinity for the androgen receptor: 6>7>5>DHT. Surprisingly compounds 4 and 8 did not bind to the androgen receptor. The overall data indicate that all synthesized compounds are inhibitors for the enzyme 5α-reductase present in the hamster prostate. In contrast, compounds 5, 6 and 7, which have a cyclohexyl group in the side chain showed a high affinity for the androgen receptor.

The in vitro inhibitory activity of five new progesterone derivatives: 17alpha-hydroxy-16beta-methylpregna-1,4,6-triene-3,20-dione 1; 16beta-methyl-17alpha-toluoyloxypregna-1,4,6-triene-3,20-dione 2; 17alpha-hydroxy-6-methylenepregn-4-ene-3,20-dione 3; 6-methylene-17alpha-toluoyloxypregn-4ene-3,20-dione 4 and 17alpha-(p-bromobenzoyloxy)-6-methylenepregn-4-ene-3,20-dione 5 was determined. These compounds were evaluated as 5alpha-reductase inhibitors as well as antagonists for the androgen receptor. Compounds 1, 2, 3, 4 and 5 showed the following inhibitory activity for the 5alpha-reductase enzyme with IC(50) values of: 1 (1.65 microM), 2 (10 microM), 3 (19 nM), 4 (100 nM) and 5 (100 nM). The results of this study also showed the effect of increasing concentrations of the novel steroids upon [(3)H]dihydrotestosterone binding to androgen receptors from male hamster prostate. The K(i) values for compounds 1, 2, 3, 4, 5 and dihydrotestosterone showed the following order of affinity for the androgen receptor: 4>5>dihydrotestosterone>2>3>1. The overall data indicated that all synthesized compounds 1, 2, 3, 4 and 5 are inhibitors of the 5alpha-reductase enzyme present in the hamster prostate. In addition compounds 1, 2, 3, 4 and 5 also presented an affinity for the androgen receptor.