TY - JOUR
T1 - Synthesis and evaluation of imidazolylmethylenetetrahydronaphthalenes and imidazolylmethyleneindanes
T2 - Potent inhibitors of aldosterone synthase
AU - Ulmschneider, Sarah
AU - Müller-Vieira, Ursula
AU - Mitrenga, Markus
AU - Hartmann, Rolf W.
AU - Oberwinkler-Marchais, Sandrine
AU - Klein, Christian D.
AU - Bureik, Matthias
AU - Bernhardt, Rita
AU - Antes, Iris
AU - Lengauer, Thomas
PY - 2005/3/24
Y1 - 2005/3/24
N2 - 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 11β-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 (IC50 = 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 Bb was found to be a highly potent CYP11B2 inhibitor (IC50 = 4 nM) showing a 5-fold selectivity for CYP11B1 (IC50 = 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.
AB - 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 11β-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 (IC50 = 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 Bb was found to be a highly potent CYP11B2 inhibitor (IC50 = 4 nM) showing a 5-fold selectivity for CYP11B1 (IC50 = 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.
UR - http://www.scopus.com/inward/record.url?scp=20144370140&partnerID=8YFLogxK
U2 - 10.1021/jm049600p
DO - 10.1021/jm049600p
M3 - Article
C2 - 15771425
AN - SCOPUS:20144370140
SN - 0022-2623
VL - 48
SP - 1796
EP - 1805
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 6
ER -