Heteroaryl-substituted naphthalenes and structurally modified derivatives: selective inhibitors of CYP11B2 for the treatment of congestive heart failure and myocardial fibrosis.

摘要

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.