Heteroaryl-substituted naphthalenes and structurally modified derivatives: selective inhibitors of CYP11B2 for the treatment of congestive heart failure and myocardial fibrosis.
Recently we proposed inhibition of aldosterone synthase (CYP11B2) as a novel strategy for the treatment of congestive heart failure and myocardial fibrosis. In this study the synthesis and biological evaluation of heteroaryl-substituted naphthalenes and quinolines (1-31) is described. Key step for the preparation of the compounds was a Suzuki cross-coupling. Activity of the compounds was determined in vitro using human CYP11B2 and selectivity was evaluated toward the human steroidogenic enzymes CYP11B1, CYP19, and CYP17. A large number of highly active and selective inhibitors of CYP11B2 was identified. The most active inhibitor was the 6-cyano compound 8 (IC50 = 3 nM) showing a competitive type of inhibition (K(i) value = 1.9 nM). The 6-ethoxy derivative 5 was found to be the most selective CYP11B2 inhibitor (IC50 = 12 nM; K(i) value = 8 nM; CYP11B1 IC50 = 5419 nM; selectivity factor = 451), showing no inhibition of human CYP3A4 (50 nM) and CYP2D6 (20 nM). Docking and molecular dynamics studies using our homology modeled CYP11B2 structure with selected compounds were performed. Caco-2 cell experiments revealed a large number of medium and highly permeable compounds and metabolic studies with 2 using rat liver microsomes showed sufficient stability.
Voets
Marieke
M
8.2 Pharmaceutical and Medicinal Chemistry, Saarland University, P.O. Box 151150, D-66041 Saarbrücken, Germany.
Antes
Iris
I
Scherer
Christiane
C
Müller-Vieira
Ursula
U
Biemel
Klaus
K
Barassin
Catherine
C
Marchais-Oberwinkler
Sandrine
S
Hartmann
Rolf W
RW
D001141:Aromatase / Q000737:chemistry / Q000378:metabolism; D047072:Aromatase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D018938:Caco-2 Cells; D002463:Cell Membrane Permeability; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005355:Fibrosis / Q000188:drug therapy; D006333:Heart Failure / Q000188:drug therapy*; D006801:Humans; D066298:In Vitro Techniques; D008099:Liver / Q000201:enzymology; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D008958:Models, Molecular; D009206:Myocardium / Q000473:pathology*; D009281:Naphthalenes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012568:Schizosaccharomyces / Q000187:drug effects / Q000201:enzymology; D013252:Steroid 11-beta-Hydroxylase / Q000037:antagonists & inhibitors / Q000737:chemistry; D013254:Steroid 17-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000737:chemistry; D013329:Structure-Activity Relationship
D047072:Aromatase Inhibitors; D009281:Naphthalenes; D001141:Aromatase; D013254:Steroid 17-alpha-Hydroxylase; D019405:Cytochrome P-450 CYP11B2; D013252:Steroid 11-beta-Hydroxylase