NOVEL 17-AZOLYL STEROIDS, POTENT INHIBITORS OF HUMAN CYTOCHROME 17-ALPHA-HYDROXYLASE-C-17,C-20-LYASE (P450(17-ALPHA)) - POTENTIAL AGENTS FOR THE TREATMENT OF PROSTATE-CANCER

A new synthetic route to a variety of novel Delta 16-17-azolyl steroid s is described: it involves the nucleophilic vinylic ''addition-elimin ation'' substitution reaction of 3 eta-acetoxy-17-chloro-16-formylandr osta-5,16-diene (2) and azolyl nucleophiles. Some of these novel Delta (16)-17-azolyl steroids, 6, 17, 19, and 27-29, prepared in good overal l yields, are very potent inhibitors of human and rat testicular P450( 17 alpha). They are shown to be noncompetitive and appear to be slow-b inding inhibitors of human P450(17 alpha). The most potent compounds a re 3 a-hydroxy-17-(1H-imidazol-1-yl)androsta-5,16-diene (17), 3 roxy-1 7-(1H-1,2,3-triazol-1-yl)androsta-5,16-diene (19), and 17-(1H-imidazol -1-yl)androsta-4,16-dien-3-one (28), with K-i values of 1.2, 1.4, and 1.9 nM, respectively, being 20-32 times more potent than ketoconazole (K-i = 38 nM). Spectroscopic studies with a modified form of human P45 0(17 alpha) indicate that the inhibition process involves binding of s teroidal azole nitrogen to the heme iron of the enzyme. Furthermore, s ome of these potent P450(17 alpha) inhibitors (27-29) are also powerfu l inhibitors of steroid 5 alpha-reductase, and others (17 and 19) appe ar to exhibit strong antiandrogenic activity in cultures of the LNCaP human prostatic cancer cell line. These novel compounds with impressiv e dual biological activities make them strong candidates for developme nt as therapeutic agents for treatment of prostate cancer and other di sease states which depend on androgens.