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

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.

• Authors: Luc Roumen, Joris W Peeters, Judith M A Emmen, Ilona P E Beugels, Erica M G Custers, Marcel de Gooyer, Ralf Plate, Koen Pieterse, Peter A J Hilbers, Jos F M Smits, Jef A J Vekemans, Dirk Leysen, Harry C J Ottenheijm, Henk M Janssen, J J Rob Hermans
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 53 Issue 4 Pg. 1712-25 (Feb 25 2010) ISSN: 1520-4804 [Electronic] United States
• PMID: 20121113 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 4-((5-phenyl-1H-imidazol-1-yl)methyl)benzonitrile
• Benzyl Compounds
• Imidazoles
• 18-Hydroxycorticosterone
• Cytochrome P-450 CYP11B2
• Fadrozole

Topics

• 18-Hydroxycorticosterone (chemistry)
• Animals
• Benzyl Compounds (chemical synthesis, chemistry, pharmacology)
• Catalytic Domain
• Cell Line
• Cricetinae
• Cricetulus
• Cytochrome P-450 CYP11B2 (antagonists & inhibitors, chemistry)
• Fadrozole (chemistry)
• Humans
• Imidazoles (chemical synthesis, chemistry, pharmacology)
• Models, Molecular
• Molecular Dynamics Simulation
• Protein Binding
• Stereoisomerism
• Structure-Activity Relationship