title: 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.affiliation: BioModeling and bioInformatics, Eindhoven University of Technology, PO Box 513, Eindhoven 5600 MB, The Netherlands.
authors.forename: Luc
authors.initials: L
authors.lastname: Roumen
authors.forename: Joris W
authors.initials: JW
authors.lastname: Peeters
authors.forename: Judith M A
authors.initials: JM
authors.lastname: Emmen
authors.forename: Ilona P E
authors.initials: IP
authors.lastname: Beugels
authors.forename: Erica M G
authors.initials: EM
authors.lastname: Custers
authors.forename: Marcel
authors.initials: M
authors.lastname: de Gooyer
authors.forename: Ralf
authors.initials: R
authors.lastname: Plate
authors.forename: Koen
authors.initials: K
authors.lastname: Pieterse
authors.forename: Peter A J
authors.initials: PA
authors.lastname: Hilbers
authors.forename: Jos F M
authors.initials: JF
authors.lastname: Smits
authors.forename: Jef A J
authors.initials: JA
authors.lastname: Vekemans
authors.forename: Dirk
authors.initials: D
authors.lastname: Leysen
authors.forename: Harry C J
authors.initials: HC
authors.lastname: Ottenheijm
authors.forename: Henk M
authors.initials: HM
authors.lastname: Janssen
authors.forename: J J Rob
authors.initials: JJ
authors.lastname: Hermans
mesh_terms: D015069:18-Hydroxycorticosterone / Q000737:chemistry; D000818:Animals; D001593:Benzyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D002460:Cell Line; D006224:Cricetinae; D003412:Cricetulus; D019405:Cytochrome P-450 CYP11B2 / Q000037:antagonists & inhibitors* / Q000737:chemistry; D017316:Fadrozole / Q000737:chemistry; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D011485:Protein Binding; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: C547952:4-((5-phenyl-1H-imidazol-1-yl)methyl)benzonitrile; D001593:Benzyl Compounds; D007093:Imidazoles; D015069:18-Hydroxycorticosterone; D019405:Cytochrome P-450 CYP11B2; D017316:Fadrozole