title: Synthesis and evaluation of imidazolylmethylenetetrahydronaphthalenes and imidazolylmethyleneindanes: potent inhibitors of aldosterone synthase.
abstract: Elevated plasma aldosterone levels play a detrimental role in certain forms of congestive heart failure and myocardial fibrosis. We proposed aldosterone synthase (CYP11B2) as a novel target for the treatment of these diseases. In this study, the synthesis and biological evaluation of substituted E- and Z-imidazolylmethylenetetrahydronaphthalenes and E- and Z-imidazolylmethyleneindanes (compounds 1a,b-9a,b) is described. The compounds were prepared by a Wittig-like reaction. They were tested for activity using bovine CYP11B and human CYP11B2 expressed in fission yeast and V79 MZh cells. Selectivity was determined toward human CYP11B1, CYP19, and CYP17. Especially in the case of CYP11B1 (steroid 11beta-hydroxylase), selectivity is a crucial issue, since sequence homology between this enzyme and the target enzyme is very high (93%). On the basis of the X-ray structure of human CYP2C9, a protein model of CYP11B2 was developed and docking experiments with the title compounds were performed. The biological results revealed highly potent inhibitors of CYP11B2 (IC(50) = 4-93 nM). The Z-isomers usually were more active than the corresponding E-isomers. Different inhibitory profiles could be observed: rather selective inhibitors of CYP11B1, dual inhibitors of both enzymes, and rather selective inhibitors of CYP11B2. The chloro derivative 8b was found to be a highly potent CYP11B2 inhibitor (IC(50) = 4 nM) showing a 5-fold selectivity for CYP11B1 (IC(50) = 20 nM). This compound could be an interesting lead for further optimization as a therapeutic agent. It also could be used as well as the CYP11B1 selective compounds as a pharmacological tool.
authors.affiliation: 8.5 Pharmaceutical and Medicinal Chemistry and 8.8 Biochemistry, Saarland University, P.O. Box 15 11 50, D-66041 Saarbrücken, Germany.
authors.forename: Sarah
authors.initials: S
authors.lastname: Ulmschneider
authors.forename: Ursula
authors.initials: U
authors.lastname: Müller-Vieira
authors.forename: Markus
authors.initials: M
authors.lastname: Mitrenga
authors.forename: Rolf W
authors.initials: RW
authors.lastname: Hartmann
authors.forename: Sandrine
authors.initials: S
authors.lastname: Oberwinkler-Marchais
authors.forename: Christian D
authors.initials: CD
authors.lastname: Klein
authors.forename: Matthias
authors.initials: M
authors.lastname: Bureik
authors.forename: Rita
authors.initials: R
authors.lastname: Bernhardt
authors.forename: Iris
authors.initials: I
authors.lastname: Antes
authors.forename: Thomas
authors.initials: T
authors.lastname: Lengauer
mesh_terms: D000818:Animals; D001141:Aromatase / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001189:Aryl Hydrocarbon Hydroxylases / Q000737:chemistry; D002417:Cattle; D002460:Cell Line; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D065729:Cytochrome P-450 CYP2C9; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007192:Indenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D012568:Schizosaccharomyces / Q000187:drug effects / Q000201:enzymology; D013237:Stereoisomerism; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors; D013329:Structure-Activity Relationship; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: C500061:5-((5-chloro-2,3-dihydro-1H-inden-1-ylidene)methyl)-1H-imidazole; D047072:Aromatase Inhibitors; D007093:Imidazoles; D007189:Indans; D007192:Indenes; D013764:Tetrahydronaphthalenes; C450260:CYP2C9 protein, human; D065729:Cytochrome P-450 CYP2C9; D001141:Aromatase; D001189:Aryl Hydrocarbon Hydroxylases; D013254:Steroid 17-alpha-Hydroxylase; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase