Synthesis, biological evaluation, and molecular modeling of 1-benzyl-1H-imidazoles as selective inhibitors of aldosterone synthase (CYP11B2).

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Roumen L, Peeters JW, Emmen JM, Beugels IP, Custers EM, de Gooyer M, Plate R, Pieterse K, Hilbers PA, Smits JF, Vekemans JA, Leysen D, Ottenheijm HC, Janssen HM, Hermans JJ

Synthesis, biological evaluation, and molecular modeling of 1-benzyl-1H-imidazoles as selective inhibitors of aldosterone synthase (CYP11B2).

J Med Chem. 2010 Feb 25;53(4):1712-25. doi: 10.1021/jm901356d.

PubMed ID

20121113 [ View in PubMed

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Abstract

Reducing aldosterone action is beneficial in various major diseases such as heart failure. Currently, this is achieved with mineralocorticoid receptor antagonists, however, aldosterone synthase (CYP11B2) inhibitors may offer a promising alternative. In this study, we used three-dimensional modeling of CYP11B2 to model the binding modes of the natural substrate 18-hydroxycorticosterone and the recently published CYP11B2 inhibitor R-fadrozole as a rational guide to design 44 structurally simple and achiral 1-benzyl-1H-imidazoles. Their syntheses, in vitro inhibitor potencies, and in silico docking are described. Some promising CYP11B2 inhibitors were identified, with our novel lead MOERAS115 (4-((5-phenyl-1H-imidazol-1-yl)methyl)benzonitrile) displaying an IC(50) for CYP11B2 of 1.7 nM, and a CYP11B2 (versus CYP11B1) selectivity of 16.5, comparable to R-fadrozole (IC(50) for CYP11B2 6.0 nM, selectivity 19.8). Molecular docking of the inhibitors in the models enabled us to generate posthoc hypotheses on their binding modes, providing a valuable basis for future studies and further design of CYP11B2 inhibitors.

DrugBank Data that Cites this Article

Binding Properties

Drug	Target	Property	Measurement	pH	Temperature (°C)
Etomidate	Cytochrome P450 11B1, mitochondrial	IC 50 (nM)	0.5	N/A	N/A	Details
Etomidate	Cytochrome P450 11B2, mitochondrial	IC 50 (nM)	1.7	N/A	N/A	Details