143426-59-9Relevant articles and documents
General base-guanidinium cooperation in bifunctional artificial phosphodiesterases
Salvio, Riccardo,Cacciapaglia, Roberta,Mandolini, Luigi
experimental part, p. 5438 - 5443 (2011/08/05)
Artificial phosphodiesterases that combine a guanidinium unit with a general base connected by a m-xylylene linker catalyze the transesterification of the RNA model compound 2-hydroxypropyl p-nitrophenyl phosphate (HPNP). The bifunctional catalysts presented in this work show varying extents of cooperation between catalytic units and a rate enhancement of 4 ×10 4 in the most favorable case.
Synthesis, Biological Evaluation, and Molecular Modeling of 1 -Benzyl-1H-imidazoles as Selective Inhibitors of Aldosterone Synthase (CYP11B2)
Roumen, Luc,Peeters, Joris W.,Emmen, Judith M. A.,Beugels, Ilona P. E.,Custers, Erica M. G.,De Gooyer, Marcel,Plate, Ralf,Pieterse, Koen,Hilbers, Peter A. J.,Smits, Jos F. M.,Vekemans, Jef A. J.,Leysen, Dirk,Ottenheijm, Harry C. J.,Janssen, Henk M.,Rob Hermans
experimental part, p. 1712 - 1725 (2010/07/17)
Reducing aldosterone action is beneficial in various major diseases such as heart failure. Currently, this is achieved, with mineralocorticoid, receptor antagonists, however, aldosterone synthase (CYP 11B2) 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, MOERAS 115 (4-((5-phenyl-1H-imidazol-1-yl)methyl) benzonitrile) displaying an IC50 for CYP11B2 of 1.7 nM, and a CYP11B2 (versus CYP11B1) selectivity of 16.5, comparable to R-fadrozole (IC 50 for CYP11B26.0 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.
A structure-Permeability study of small drug-like molecules
Fichert, Thomas,Yazdanian, Mehran,Proudfoot, John R.
, p. 719 - 722 (2007/10/03)
A systematic structure-permeability relationship study on a set of small drug-like molecules with log D values in the range -2.5 to 3 and carrying a diverse array of functionality reveals that the compounds with log D>0 and 3 are highly permeable. Surprisingly, several tetrazole derivatives were found to be substrates for efflux pump(s).
Aromatic hydrazides as specific inhibitors of bovine serum amine oxidase
Artico,Silvestri,Stefancich,Avigliano,Di Giulio,Maccarrone,Agostinelli,Mondovi,Morpurgo
, p. 219 - 228 (2007/10/02)
New hydrazides were synthesized in search for specific inhibitors of bovine serum amine oxidase: a series of benzoic and phenylacetic acid hydrazides containing the 1H-imidazol-1-yl or the 1H-imidazol-1-ylmethyl group as (o,m,p)-substituent in the phenyl ring; an analogous series of p-substituted phenylhydrazides with 5 or 6-membered heterocyclic ring as substituent, and a series of similar phenylpropionic hydrazides. The longer and more flexible phenylacetic hydrazides, and to a somewhat lesser extent the phenylpropionic ones, were better specific inhibitors of bovine serum amine oxidase than the benzoic hydrazides, which were also bound by the enzyme with high affinity, but at a slow rate. Derivatives with p- and m-substituents were more reactive than the o-substituted ones. The chemical nature of the substituent was less important than its position in the phenyl ring and the presence of methylene spacers. These data point to the presence of a hydrophobic site at short distance from the protein carbonyl cofactor, so that simultaneous interaction of the 2 ends of the inhibitor molecule can occur at the 2 sites. The presence of the hydrophobic site was confirmed by the capability of some molecule deprived of the hydrazidic group to act as mild inhibitors. All hydrazides were less reactive by 2-3 orders of magnitude towards pig kidney diamine oxidase and FAD-dependent monoamine oxidase from rat brain mitochondria, while the other compounds showed similar inhibition power against all proteins. The specificity for the bovine enzyme seems therefore to be related to the concerted action of the 2 moieties of the inhibitor molecule.
