Synthesis, biological evaluation, and molecular modeling of 1-benzyl-1H-imidazoles as selective inhibitors of aldosterone synthase (CYP11B2).
| Title: | Synthesis, biological evaluation, and molecular modeling of 1-benzyl-1H-imidazoles as selective inhibitors of aldosterone synthase (CYP11B2). |
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| Authors: | Roumen L; BioModeling and bioInformatics, Eindhoven University of Technology, PO Box 513, Eindhoven 5600 MB, The Netherlands.; 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 |
| Source: | Journal of medicinal chemistry [J Med Chem] 2010 Feb 25; Vol. 53 (4), pp. 1712-25. |
| Publication Type: | Journal Article; Research Support, Non-U.S. Gov't |
| Language: | English |
| Journal Info: | Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE |
| Imprint Name(s): | Publication: Washington Dc : American Chemical Society; Original Publication: [Easton, Pa.] : American Chemical Society, [c1963- |
| MeSH Terms: | Models, Molecular*; Benzyl Compounds/*chemical synthesis ; Cytochrome P-450 CYP11B2/*antagonists & inhibitors ; Imidazoles/*chemical synthesis; 18-Hydroxycorticosterone/chemistry ; Benzyl Compounds/chemistry ; Benzyl Compounds/pharmacology ; Cytochrome P-450 CYP11B2/chemistry ; Fadrozole/chemistry ; Imidazoles/chemistry ; Imidazoles/pharmacology ; Animals ; Catalytic Domain ; Cell Line ; Cricetinae ; Cricetulus ; Humans ; Molecular Dynamics Simulation ; Protein Binding ; Stereoisomerism ; Structure-Activity Relationship |
| 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. |
| Substance Nomenclature: | 0 (4-((5-phenyl-1H-imidazol-1-yl)methyl)benzonitrile); 0 (Benzyl Compounds); 0 (Imidazoles); 561-65-9 (18-Hydroxycorticosterone); EC 1.14.15.4 (Cytochrome P-450 CYP11B2); H3988M64PU (Fadrozole) |
| Entry Date(s): | Date Created: 20100204 Date Completed: 20100323 Latest Revision: 20141120 |
| Update Code: | 20260130 |
| DOI: | 10.1021/jm901356d |
| PMID: | 20121113 |
| Database: | MEDLINE |
Journal Article; Research Support, Non-U.S. Gov't