title: Pyridyl substituted benzocycloalkenes: new inhibitors of 17 alpha-hydroxylase/17,20-lyase (P450 17 alpha).
abstract: Compounds capable of inhibiting 17 alpha-hydroxylase/17,20-lyase (P450 17 alpha) are of great interest for the therapy of prostatic cancer since they block androgen biosynthesis. In order to evaluate the inhibitory activity of a series of benzocycloalkenes developed in our group, an in vitro assay was established using rat testicular microsomes as source of the enzyme, non labelled progesterone as substrate and a HPLC procedure for separation of the steroids. The inhibitory activities of 33 test compounds were compared to ketoconazole (IC50 67 microM), a known inhibitor of P450 17 alpha, which recently has been successfully used in prostate cancer patients. Several compounds of the present study were stronger inhibitors of P450 17 alpha than ketoconazole. The most active compounds were compound 12(5-methoxy-2-(4-pyridylmethyl)-1-tetralone: IC50 13 microM) and compound 13(5-methoxy-2-(4-pyridyl)-1-tetralone: IC50 13 microM).
authors.affiliation: Fachrichtung 12.1 Pharmazeutische Chemie, Universität des Saarlandes, Saarbrücken, F.R.G.
authors.forename: T
authors.initials: T
authors.lastname: Sergejew
authors.forename: R W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000446:Aldehyde-Lyases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D008861:Microsomes / Q000201:enzymology; D015394:Molecular Structure; D011374:Progesterone / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy / Q000201:enzymology; D011725:Pyridines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013254:Steroid 17-alpha-Hydroxylase; D013250:Steroid Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013329:Structure-Activity Relationship; D013737:Testis / Q000201:enzymology*; D013764:Tetrahydronaphthalenes / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D065607:Cytochrome P-450 Enzyme Inhibitors; D011725:Pyridines; D013764:Tetrahydronaphthalenes; C001952:3-(6-chloro-3-methyl-2-indenyl)pyridine; D011374:Progesterone; C001953:SU 10603; D003577:Cytochrome P-450 Enzyme System; D013250:Steroid Hydroxylases; D013254:Steroid 17-alpha-Hydroxylase; D000446:Aldehyde-Lyases; D007654:Ketoconazole