Discovery of selective CYP11B2 (aldosterone synthase) inhibitors for the therapy of congestive heart failure and myocardial fibrosis.
An increased aldosterone concentration due to congestive heart failure leads to a further progression of the disease as well as to myocardial fibrosis. To interfere with these fatal processes selective inhibition of aldosterone synthase (CYP11B2) is required. CYP11B1, a key enzyme in glucocorticoid biosynthesis showing a high homology to the target enzyme (>93%), must not be inhibited. Screening of our P450 inhibitor library for inhibition of bovine aldosterone synthase resulted in a high number of compounds showing reasonable inhibition. In the next step substances were tested for oral absorption using two artificial membrane assays. The inhibition of human CYP11B2 was evaluated using assays in fission yeast and V79MZ cells stably expressing the active human target enzyme. For selectivity, inhibition of CYP11B1, CYP11A1, CYP17, CYP19 and CYP5 was determined. Rather potent and selective compounds obtained in this way were structurally further optimised, finally leading to inhibitors showing IC(50) values within the low nanomolar range.
Hartmann
Rolf W
RW
Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 151150, 66041, Saarbrücken, Germany. rwh@mx.uni-saarland.de
Müller
Ursula
U
Ehmer
Peter B
PB
D000818:Animals; D018938:Caco-2 Cells; D009202:Cardiomyopathies / Q000188:drug therapy; D002417:Cattle; D002460:Cell Line; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005355:Fibrosis; D006333:Heart Failure / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D007189:Indans / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D008956:Models, Chemical; D015394:Molecular Structure; D009206:Myocardium / Q000201:enzymology / Q000473:pathology*; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013764:Tetrahydronaphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D004791:Enzyme Inhibitors; D007189:Indans; D011725:Pyridines; D013764:Tetrahydronaphthalenes; D019405:Cytochrome P-450 CYP11B2