Synthesis and Evaluation of (Pyridylmethylene)tetrahydronaphthalenes/-indanes and Structurally Modified Derivatives:  Potent and Selective Inhibitors of Aldosterone Synthase

Abstract

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.

New CYP17 Hydroxylase Inhibitors: Synthesis, Biological Evaluation, QSAR, and Molecular Docking Study of New Pregnenolone Analogs

“…Our molecular docking analysis of the new analogs was based on the human CYP17 homology model , which exhibited quite similar binding patterns at the active site of CYP17. The prospective ligands were ranked according to the highest binding energy as the best conformers.…”

CYP17 Inhibitors. Annulations of Additional Rings in Methylene Imidazole Substituted Biphenyls: Synthesis, Biological Evaluation and Molecular Modelling

“…Its importance relies on the fact that it catalyzes the last step in glucocorticoid formation, namely the transformation of 11-deoxycortisol into cortisol. For the assay [19], V79MZh11B1 cells expressing human CYP11B1 were used. Both compounds showed strong inhibition of the enzyme at the tested concentrations (9: 86 and 94% at 0.2 and 2 lM; 21: 81 and 95% at 0.2 and 2 lM).…”

“…Inhibition of CYP11B1: V79MZh11B1 cells expressing the respective human enzyme were used and our assay procedure using [4-14 C]-11-deoxycorticosterone was applied [19].…”

Heteroatom insertion into 3,4-dihydro-1H-quinolin-2-ones leads to potent and selective inhibitors of human and rat aldosterone synthase

“…[26] Subsequent optimization resulted in several classes of nonsteroidal highly potent hCYP11B2 inhibitors, i.e. imidazolyl-and pyridylmethylenetetrahydronaphthalenes and -indanes, [27,28] heterocycle substituted naphthalenes, dihydronaphthalenes, [29][30][31][32] pyridinyl substituted aliphatic cycles, [33] dihydroquinolinones, [34] indolines, [35] tetrahydropyrroloquinolinone, [36,37] and phenylsulfinyl naphthalenol. [38] Recently, several compound classes derived from the anaesthetic R-etomidate or the CYP19 inhibitor Fadrozole (Chart 1) were described as inhibitors of hCYP11B2.…”