Discovery of nanomolar ligands with novel scaffolds for the histamine H4 receptor by virtual screening.

The involvement of histamine H4 receptor (H4R) in immune cells chemotaxis and mediator release makes it an attractive target for the treatment of inflammation disorders. A decade of medicinal chemistry efforts has led to several promising ligands, although the chemical structures described so far possesses a singular limited diversity. We report here the discovery of novel structures, belonging to completely different scaffolds. The virtual screening was planed as a two-steps process. First, using a "scout screening" methodology, we have experimentally probed the H4R ligand binding site using a small size chemical library with very diverse structures, and identified a hit that further assist us in refining a raw 3D homology model. Second, the refined 3D model was used to conduct a widened virtual screening. This two-steps strategy proved to be very successful, both in terms of structural diversity and hit rate (23%). Moreover, the hits have high affinity for the H4R, with most potent ligands in the nanomolar range.

Synthesis and evaluation of a 2-benzothiazolylphenylmethyl ether class of histamine H4 receptor antagonists.

Synthesis and biological evaluation of a new class of histamine H4 receptor ligands, distinct from the previously reported chemotypes, are described. A virtual screening of our corporate compound collection identified a hit with an undesired dual H3R/H4R activity. Chemical exploration led to the discovery of a more potent and selective 2-benzothiazolylphenylmethyl ether lead compound.

Improving selectivity of dopamine D3 receptor ligands.

The seminal human dopamine D3 receptor (hD3R) ligand BP 897 has shown interesting properties during clinical trials. However, its lack of selectivity towards human adrenergic receptor impedes further development. Two approaches were followed to increase hD3R selectivity. The lead optimisation succeeded, we disclose here ligands with subnanomolar potency for D3R, combined with a good selectivity for the closely related human dopamine D2 and human adrenergic alpha-1 receptors.

Homology Model Versus X-ray Structure in Receptor-based Drug Design: A Retrospective Analysis with the Dopamine D3 Receptor.

Structure-based design methods commonly used in medicinal chemistry rely on a three-dimensional representation of the receptor. However, few crystal structures are solved in comparison with the huge number of pharmaceutical targets. This often renders homology models the only information available. It is particularly true for G protein-coupled receptors (GPCRs), one of the most important targets for approved medicines and current drug discovery projects. However, very few studies have tested their validity in comparison with corresponding crystal structures, especially in a lead optimization perspective. The recent solving of dopamine D3 receptor crystal structure allowed us to assess our historical homology model. We performed a statistical analysis, by docking our in-house lead optimization library of 1500 molecules. We demonstrate here that the refined homology model suits at least as well as the X-ray structure. It is concluded that when the crystal structure of a given GPCR is not available, homology modeling can be an excellent surrogate to support drug discovery efforts.

Synthesis and evaluation of amides surrogates of dopamine D3 receptor ligands.

Isosteric replacement of the amide function and modulation of the arylpiperazine moiety of known dopamine D3 receptor ligands led to potent and selective compounds. Enhanced bioavailability and preferential brain distribution make compound 6c a good candidate for pharmacological and clinical evaluation.

Refined docking as a valuable tool for lead optimization: application to histamine H3 receptor antagonists.

Drug-discovery projects frequently employ structure-based information through protein modeling and ligand docking, and there is a plethora of reports relating successful use of them in virtual screening. Hit/lead optimization, which represents the next step and the longest for the medicinal chemist, is very rarely considered. This is not surprising because lead optimization is a much more complex task. Here, a homology model of the histamine H(3) receptor was built and tested for its ability to discriminate ligands above a defined threshold of affinity. In addition, drug safety is also evaluated during lead optimization, and "antitargets" are studied. So, we have used the same benchmarking procedure with the HERG channel and CYP2D6 enzyme, for which a minimal affinity is strongly desired. For targets and antitargets, we report here an accuracy as high as at least 70%, for ligands being classified above or below the chosen threshold. Such a good result is beyond what could have been predicted, especially, since our test conditions were particularly stringent. First, we measured the accuracy by means of AUC of ROC plots, i. e. considering both false positive and false negatives. Second, we used as datasets extensive chemical libraries (nearly a thousand ligands for H(3)). All molecules considered were true H(3) receptor ligands with moderate to high affinity (from microM to nM range). Third, the database is issued from concrete SAR (Bioprojet H(3) BF2.649 library) and is not simply constituted by few active ligands buried in a chemical catalogue.

A solid phase parallel synthesis of diverse amides as dopamine D3 receptor ligands.

A solid phase parallel synthesis using SynPhase technology was used to couple a series of 21 carboxylic with three different 4-(4-arylpiperazinyl)butanamines. The resulting library was evaluated as dopamine D(3) receptor ligands giving rise to several compounds with affinities in the low nanomolar concentration range (9e and 9n with binding affinities at D(3) receptors of 0.10 and 0.35 nM respectively).

Strategies for access to enantiomerically pure ecadotril, dexecadotril and fasidotril: a review.

Ecadotril and dexecadotril are powerful and selective inhibitors of neprilysin (NEP, EC 3.4.24.11) and are being developed as therapeutic agents, since they behave as prodrugs of the enantiomers of thiorphan. They exhibit different pharmaceutical profiles (intestinal antisecretatory action for the (R) enantiomer, i.e. dexecadotril, and cardiovascular activity for the (S) enantiomer, i.e. ecadotril). Fasidotril is a related compound which has special interest as an equipotent dual inhibitor of NEP and ACE (EC 3.4.15.1). This behavior confers on fasidotril powerful pharmaceutical properties in the cardiovascular field. This review deals with various synthetic approaches, either published or patented, for access to the enantiomerically pure or highly enriched forms of these drugs. Thus, different methods have been studied, which are taken from different methodologies of resolution procedures and asymmetric synthesis, namely : i- Synthesis from a chiron from the chiral pool ii- Chemical resolution of racemic precursors iii- Enzymatic resolution and desymmetrization of meso starting materials iv- Asymmetric synthesis, including enantioselective catalytic hydrogenation, alkaloid catalyzed asymmetric Michael additions, and diastereoselective alkylation of a chiral derivative. Some of these methods are used in industrial processes leading to the indicated compounds.