title: Synthesis, biological evaluation, and molecular modeling studies of methylene imidazole substituted biaryls as inhibitors of human 17alpha-hydroxylase-17,20-lyase (CYP17)--part II: Core rigidification and influence of substituents at the methylene bridge.
abstract: Thirty-five novel substituted imidazolyl methylene biphenyls have been synthesized as CYP17 inhibitors for the potential treatment of prostate cancer. Their activities have been tested with recombinant human CYP17 expressed in Escherichia coli. Promising compounds were tested for selectivity against CYP11B1, CYP11B2, and hepatic CYP enzymes 3A4, 1A2, 2B6 and 2D6. The core rigidified compounds (30-35) were the most active ones, being much more potent than Ketoconazole and reaching the activity of Abiraterone. However, they were not very selective. Another rather potent and more selective inhibitor (compound 23, IC(50)=345 nM) was further examined in rats regarding plasma testosterone levels and pharmacokinetic properties. Compared to the reference Abiraterone, 23 was more active in vivo, showed a longer plasma half-life (10h) and a higher bioavailability. Using our CYP17 homology protein model, docking studies with selected compounds were performed to study possible interactions between inhibitors and amino acid residues of the active site.
authors.affiliation: Pharmaceutical and Medicinal Chemistry, Saarland University, PO Box 151150, D-66041 Saarbrücken, Germany.
authors.forename: Qingzhong
authors.initials: Q
authors.lastname: Hu
authors.forename: Matthias
authors.initials: M
authors.lastname: Negri
authors.forename: Kerstin
authors.initials: K
authors.lastname: Jahn-Hoffmann
authors.forename: Yan
authors.initials: Y
authors.lastname: Zhuang
authors.forename: Sureyya
authors.initials: S
authors.lastname: Olgen
authors.forename: Marc
authors.initials: M
authors.lastname: Bartels
authors.forename: Ursula
authors.initials: U
authors.lastname: Müller-Vieira
authors.forename: Thomas
authors.initials: T
authors.lastname: Lauterbach
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
mesh_terms: D000818:Animals; D001665:Binding Sites; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D017433:Protein Structure, Secondary; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013055:Spectrophotometry, Infrared; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors*; D013739:Testosterone / Q000097:blood
chemical_list: D001713:Biphenyl Compounds; D004791:Enzyme Inhibitors; D007093:Imidazoles; D013739:Testosterone; D013254:Steroid 17-alpha-Hydroxylase