Synthesis and evaluation of (pyridylmethylene)tetrahydronaphthalenes/-indanes and structurally modified derivatives: potent and selective inhibitors of aldosterone synthase.
Elevated aldosterone levels are key effectors for the development and progression of congestive heart failure and myocardial fibrosis. Recently, we proposed inhibition of aldosterone synthase (CYP11B2) as an innovative strategy for the treatment of these diseases. In this study, the synthesis and biological evaluation of E- and Z-(pyridylmethylene)tetrahydronaphthalenes and -indanes (1a,b-38a) is described. The activity of the compounds was determined using human CYP11B2, and the selectivity was evaluated toward the human steroidogenic enzymes CYP11B1, CYP19, and CYP17. The biological results revealed a few rather selective inhibitors of CYP11B1, some compounds inhibiting both CYP11B1 and CYP11B2, and a large number of highly selective inhibitors of CYP11B2. The most active inhibitor was the 3-pyridyl compound 5a (IC(50) = 7 nM). The pyrimidyl-substituted derivative 28a was found to be the most selective CYP11B2 inhibitor (IC(50) = 27 nM) in this series, showing a 120-fold selectivity for CYP11B1 (IC(50) = 3179 nM). Molecular modeling, i.e., examination of the electronic and steric features of selected compounds and homology modeling and docking, was used to understand the structure-activity/-selectivity relationships.
Ulmschneider
Sarah
S
FR 8.2 Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 15 11 50, D-66041 Saarbrücken, Germany.
Müller-Vieira
Ursula
U
Klein
Christian D
CD
Antes
Iris
I
Lengauer
Thomas
T
Hartmann
Rolf W
RW
D000305:Adrenal Cortex Hormones / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D001141:Aromatase / Q000378:metabolism; D002460:Cell Line; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis; D004926:Escherichia coli / Q000187:drug effects / Q000201:enzymology; D006801:Humans; D066298:In Vitro Techniques; D007189:Indans / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D008968:Molecular Conformation; D010920:Placenta / Q000648:ultrastructure; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; 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
D000305:Adrenal Cortex Hormones; D007189:Indans; D011725:Pyridines; D013764:Tetrahydronaphthalenes; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase