TY - JOUR
T1 - Synthesis, Biological Evaluation, and Molecular Modeling of 1-Benzyl-1H-imidazoles as Selective Inhibitors of Aldosterone Synthase (CYP11B2)
AU - Roumen, Luc
AU - Peeters, Joris W.
AU - Emmen, Judith M. A.
AU - Beugels, Ilona P. E.
AU - Custers, Erica M. G.
AU - De Gooyer, Marcel
AU - Plate, Ralf
AU - Pieterse, Koen
AU - Hilbers, Peter A. J.
AU - Smits, Jos F. M.
AU - Vekemans, Jef A. J.
AU - Leysen, Dirk
AU - Ottenheijm, Harry C. J.
AU - Jannsen, Henk M.
AU - Hermans, J. J. Rob
PY - 2010/2/25
Y1 - 2010/2/25
N2 - Reducing aldosterone action is beneficial in various major diseases such as heart failure. Currently, flits is achieved with mineralocorticoid receptor antagonists, however, aldosterone synthase (CYP11B2) inhibitors may offer a promising alternative. In this study, WC 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-y1)methyl)benzonitrile) displaying an IC50 for CYP11B2 of 1.7 nM, and a CYP11B2 (versus CYP11B1) selectivity of 16.5, comparable to R-fadrozole (IC50 for CYP11B2 6.0 nM. Selectivity 19.8). Molecular docking of the Inhibitors in the models enabled us to generate posthoc hypotheses oil their binding modes, providing a Valuable basis for future Studies and further design of CYP11B2 inhibitors.
AB - Reducing aldosterone action is beneficial in various major diseases such as heart failure. Currently, flits is achieved with mineralocorticoid receptor antagonists, however, aldosterone synthase (CYP11B2) inhibitors may offer a promising alternative. In this study, WC 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-y1)methyl)benzonitrile) displaying an IC50 for CYP11B2 of 1.7 nM, and a CYP11B2 (versus CYP11B1) selectivity of 16.5, comparable to R-fadrozole (IC50 for CYP11B2 6.0 nM. Selectivity 19.8). Molecular docking of the Inhibitors in the models enabled us to generate posthoc hypotheses oil their binding modes, providing a Valuable basis for future Studies and further design of CYP11B2 inhibitors.
U2 - 10.1021/jm901356d
DO - 10.1021/jm901356d
M3 - Article
C2 - 20121113
SN - 0022-2623
VL - 53
SP - 1712
EP - 1725
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
IS - 4
ER -