Molecular Interactions of New Pregnenedione Derivatives

• Published in: Chemical & Pharmaceutical Bulletin Vol. 51; no. 10; pp. 1132 - 1136
• Main Authors: Bratoeff, Eugene, Ramírez, Elena, Flores, Eugenio, Valencia, Norma, Sánchez, Mauricio, Heuze, Ivonne, Cabeza, Marisa
• Format: Journal Article
• Language: English; Japanese
• Published: TOKYO The Pharmaceutical Society of Japan 01.10.2003; Pharmaceutical Society of Japan; Pharmaceutical Soc Japan; Maruzen; Japan Science and Technology Agency
• Subjects: 3-Oxo-5-alpha-Steroid 4-Dehydrogenase - metabolism; 5-alpha Reductase Inhibitors; 5α-reductase inhibition; androgen receptor; Animals; Biological and medical sciences; Chemistry; Chemistry, Medicinal; Chemistry, Multidisciplinary; Cricetinae; Dose-Response Relationship, Drug; Drug Interactions - physiology; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - metabolism; Enzyme Inhibitors - pharmacology; Hormones. Endocrine system; Life Sciences & Biomedicine; Male; Medical sciences; Mesocricetus; novel steroid; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Physical Sciences; pregnenedione derivative; Progesterone - chemical synthesis; Progesterone - metabolism; Progesterone - pharmacology; prostate; Prostate - drug effects; Prostate - metabolism; Science & Technology; 5 alpha-reductase inhibition; BENIGN PROSTATIC HYPERPLASIA; androgen receptor; novel steroid; MEN; FINASTERIDE; prostate; pregnenedione derivative; MALE PSEUDOHERMAPHRODITISM; 5ALPHA-REDUCTASE DEFICIENCY; 5-ALPHA-REDUCTASE INHIBITORS; DIHYDROTESTOSTERONE; Steroid; Ketol; Antihormone; Dienone; 5α-reductase inhibition; Structure activity relation; Pregnenedione derivatives; Bromine Organic compounds; Antagonist; Chemical synthesis; Acylate; 3-Oxo-5α-steroid 4-dehydrogenase; Enzyme; Rodentia; Enzyme inhibitor; In vitro; Vertebrata; Mammalia; Androgen receptor; Affinity; Oxidoreductases; Enone; Prostate; Hamster; Hormonal receptor
• ISSN: 0009-2363; 1347-5223
• DOI: 10.1248/cpb.51.1132

The in vitro inhibitory activity of five new progesterone derivatives: 17α-hydroxy-16β-methylpregna-1,4,6-triene-3,20-dione 1; 16β-methyl-17α-toluoyloxypregna-1,4,6-triene-3,20-dione 2; 17α-hydroxy-6-methylenepregn-4-ene-3,20-dione 3; 6-methylene-17α-toluoyloxypregn-4ene-3,20-dione 4 and 17α-(p-bromobenzoyloxy)-6-methylenepregn-4-ene-3,20-dione 5 was determined. These compounds were evaluated as 5α-reductase inhibitors as well as antagonists for the androgen receptor. Compounds 1, 2, 3, 4 and 5 showed the following inhibitory activity for the 5α-reductase enzyme with IC50 values of: 1 (1.65 μM), 2 (10 μM), 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 [3H]dihydrotestosterone binding to androgen receptors from male hamster prostate. The Ki 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 5α-reductase enzyme present in the hamster prostate. In addition compounds 1, 2, 3, 4 and 5 also presented an affinity for the androgen receptor.