title: Synthesis, biological evaluation and molecular modelling studies of novel ACD- and ABD-ring steroidomimetics as inhibitors of CYP17.
abstract: Two novel classes of non-steroidal substrate mimetics were synthesised and examined for their potency as inhibitors of human CYP17. Selected compounds were tested for inhibition of hepatic CYP enzymes 3A4, 1A2, 2C9 and 2C19. The most promising compound 15 showed a good inhibition of the target enzyme (31% and 66% at 0.2 and 2 microM, respectively), and little inhibition of the most important hepatic enzyme CYP3A4 (6% and 19% inhibition at 0.2 and 2 microM, respectively) and the key enzyme of glucocorticoid biosynthesis CYP11B1 (3% and 23% inhibition at 0.2 and 2 microM, respectively). Docking studies revealed that this compound does not assume the same binding mode as steroidal ligands.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 151150, D-66041 Saarbrücken, Germany.
authors.forename: Mariano A E
authors.initials: MA
authors.lastname: Pinto-Bazurco Mendieta
authors.forename: Matthias
authors.initials: M
authors.lastname: Negri
authors.forename: Carsten
authors.initials: C
authors.lastname: Jagusch
authors.forename: Ulrike E
authors.initials: UE
authors.lastname: Hille
authors.forename: Ursula
authors.initials: U
authors.lastname: Müller-Vieira
authors.forename: Dirk
authors.initials: D
authors.lastname: Schmidt
authors.forename: Klaus
authors.initials: K
authors.lastname: Hansen
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D040761:Biomimetic Materials / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006571:Heterocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008099:Liver / Q000201:enzymology; D008958:Models, Molecular; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D011374:Progesterone / Q000737:chemistry; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D006571:Heterocyclic Compounds; D009281:Naphthalenes; D011374:Progesterone; D013254:Steroid 17-alpha-Hydroxylase