Yveline Rival

Structure-based 3D QSAR and design of novel acetylcholinesterase inhibitors

The paper describes the construction, validation and application of a structure-based 3D QSAR model of novel acetylcholinesterase (AChE) inhibitors. Initial use was made of four X-ray structures of AChE complexed with small, non-specific inhibitors to create a model of the binding of recently developed aminopyridazine derivatives. Combined automated and manual docking methods were applied to dock the co-crystallized inhibitors into the binding pocket. Validation of the modelling process was achieved by comparing the predicted enzyme-bound conformation with the known conformation in the X-ray structure. The successful prediction of the binding conformation of the known inhibitors gave confidence that we could use our model to evaluate the binding conformation of the aminopyridazine compounds. The alignment of 42 aminopyridazine compounds derived by the docking procedure was taken as the basis for a 3D QSAR analysis applying the GRID/GOLPE method. A model of high quality was obtained using the GRID water probe, as confirmed by the cross-validation method (q2LOO=0.937, q2L50% O=0.910). The validated model, together with the information obtained from the calculated AChE-inhibitor complexes, were considered for the design of novel compounds. Seven designed inhibitors which were synthesized and tested were shown to be highly active. After performing our modelling study the X-ray structure of AChE complexed with donepezil, an inhibitor structurally related to the developed aminopyirdazines, has been made available. The good agreement found between the predicted binding conformation of the aminopyridazines and the one observed for donepezil in the crystal structure further supports our developed model.

Efficient one-step synthesis of 3-amino-6-arylpyridazines

Abstract Starting from the commercially available 3-amino-6-chloropyridazine, 3-amino-6-arylpyridazines were prepared in good yields by means of a Suzuki cross-coupling reaction avoiding the somewhat lengthy four-step classic synthesis.

New Procedure for the Preparation of the Tetrazole Analogue of GABA

Abstract The hydrochloride of the tetrazolyl bioisostere of the neurotransmitter GABA can be easily prepared by means of three simple steps: a Gabriel-type substitution on 4-bromobutyronitrile with Boc2NH, a tetrazole formation by action of azidotributyltin on the cyano group and a deprotection step using gaseous HCl.

Efficient synthesis of a selective Y5 receptor antagonist

ABSTRACT A selective Y5 receptor antagonist, the hydrochloride of 2-methyl-4-pyrrolidinyl-6-[(E)-2-(3-trifluoromethylphenyl)vinyl]pyridine, can be prepared in a 7-step synthesis.

Comparative Molecular Field Analysis of Aminopyridazine Acetylcholinesterase Inhibitors

Modern methods for computer-assisted drug design fall into two major families — the indirect ligand-based methods, e.g. CoMFA or GOLPE and the direct receptor-based methods including molecular dynamics (MD) simulation, free energy pertubation (FEP) and the various docking procedures. Nowadays the ligand-based methods are widely used since they are computationally not demanding. The main problem of the ligand-based methods is the alignment of the investigated compounds. On the other hand the direct approach yields important information concerning the exact position of the ligands in the binding pocket. Since the MD and FEP methods are computationally intensive, they cannot be applied to large data sets. The faster docking programs on the other hand are at the moment not able to predict correctly the biological activity. One possibility to overcome these problems seems to be the combination of both approaches — merging the accuracy of the receptor-based strategies with the efficiency of modern 3D-QSAR techniques. This strategy has recently successfully applied by several groups1.