title: Synthesis and evaluation of 17-aliphatic heterocycle-substituted steroidal inhibitors of 17alpha-hydroxylase/C17-20-lyase (P450 17).
abstract: In the search for potent inhibitors of P450 17, the key enzyme in androgen biosynthesis, a series of steroidal inhibitors were synthesized and tested toward rat and human P450 17. Small aliphatic heterocycles (aziridine, oxirane, thiirane, diaziridine, diazirine, azetidine) were introduced into the 17beta-position of anstrost-5-en-3beta-ol. After identifying that aziridine is the most suitable functional group to coordinate with the heme iron, modifications of the steroidal skeleton were performed for further optimization. A wide range of inhibitory potencies toward P450 17 were found for the 21 test compounds. The most potent inhibitors toward the human and rat enzyme were aziridine compounds 3 (IC(50) rat: 0.21 microM, K(i) = 3 nM; IC(50) human: 0.54 microM, K(i) = 8 nM), 5 (IC(50) rat: 0.43 microM, K(i) = 7 nM; IC(50) human: 0.29 microM, K(i) = 4 nM), and 8 (21R:21S = 1:1; IC(50) rat: 0.53 microM, K(i) = 9 nM; IC(50) human: 0.40 microM, K(i) = 6 nM) which were more potent than the reference ketoconazole (IC(50) rat: 67 microM; IC(50) human: 0.74 microM). The inhibitory potency depends markedly on the stereochemistry at C20 of the inhibitors. This effect is more pronounced for the rat enzyme. Tested for selectivity, the highly potent inhibitors show poor inhibitory activity toward P450 arom, P450 scc, P450 TxA(2), and 5alpha-reductase. Tested for in vivo activity, 3 and 8 (0.019 mmol/kg) decreased the plasma testosterone concentration in rats by 81% and 84% after 2 h.
authors.affiliation: Pharmaceutical and Medicinal Chemistry and Inorganic Chemistry, University of the Saarland, P.O. Box 151150, D-66041 Saarbrücken, Germany. rwh@rz.uni-sb.de
authors.forename: R W
authors.initials: RW
authors.lastname: Hartmann
authors.forename: M
authors.initials: M
authors.lastname: Hector
authors.forename: B G
authors.initials: BG
authors.lastname: Wachall
authors.forename: A
authors.initials: A
authors.lastname: Palusczak
authors.forename: M
authors.initials: M
authors.lastname: Palzer
authors.forename: V
authors.initials: V
authors.lastname: Huch
authors.forename: M
authors.initials: M
authors.lastname: Veith
mesh_terms: D000737:Androstenols / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D002851:Chromatography, High Pressure Liquid; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007097:Imines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008861:Microsomes / Q000201:enzymology; D011284:Pregnenolone / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011863:Radioimmunoassay; D051381:Rats; D017207:Rats, Sprague-Dawley; D013056:Spectrophotometry, Ultraviolet; D013237:Stereoisomerism; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013737:Testis / Q000648:ultrastructure; D013739:Testosterone / Q000097:blood
chemical_list: C416652:22-iminopregn-5-en-3-ol; D000737:Androstenols; D004791:Enzyme Inhibitors; D007097:Imines; D013739:Testosterone; D011284:Pregnenolone; D013254:Steroid 17-alpha-Hydroxylase