Synthesis and evaluation of heteroaryl-substituted dihydronaphthalenes and indenes: potent and selective inhibitors of aldosterone synthase (CYP11B2) for the treatment of congestive heart failure and myocardial fibrosis.

Abstract

In this study, the synthesis and biological evaluation of heteroaryl-substituted dihydronaphthalenes and indenes (1-16) is described. The compounds were tested for activity by use of human CYP11B2 expressed in fission yeast and V79 MZh cells and for selectivity by use of human CYP11B1, CYP17, and CYP19. The most active inhibitor was the 6-methoxydihydronaphthalene 4 (IC(50) = 2 nM), showing a K(i) value of 1.3 nM and a competitive type of inhibition. The 5-methoxyindene 3 was found to be the most selective CYP11B2 inhibitor (IC(50) = 4 nM; CYP11B1 IC(50) = 5684 nM), which also showed only marginal inhibition of human CYP3A4 and CYP2D6. Docking and molecular dynamics studies using our homology-modeled CYP11B2 structure were performed to understand some structure-activity relationships. Caco-2 cell experiments revealed highly cell-permeable compounds, and metabolic studies with 4 using rat liver microsomes showed sufficient stability.

• Authors: Marieke Voets, Iris Antes, Christiane Scherer, Ursula Müller-Vieira, Klaus Biemel, Sandrine Marchais-Oberwinkler, Rolf W Hartmann
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 49 Issue 7 Pg. 2222-31 (Apr 06 2006) ISSN: 0022-2623 [Print] United States
• PMID: 16570918 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Indenes
• Naphthalenes
• Cytochrome P-450 CYP11B2

Topics

• Animals
• Binding Sites
• Cell Line
• Cell Membrane Permeability
• Cricetinae
• Cricetulus
• Cytochrome P-450 CYP11B2 (antagonists & inhibitors)
• Fibrosis
• Heart Failure (drug therapy)
• Humans
• Indenes (chemical synthesis, chemistry, pharmacology)
• Models, Molecular
• Myocardium (pathology)
• Naphthalenes (chemical synthesis, chemistry, pharmacology)
• Schizosaccharomyces
• Structure-Activity Relationship