Christophe Morice

Discovery, Structure–Activity Relationship, and Antiparkinsonian Effect of a Potent and Brain-Penetrant Chemical Series of Positive Allosteric Modulators of Metabotropic Glutamate Receptor 4

The metabotropic glutamate receptor 4 (mGluR4) is an emerging target for the treatment of Parkinsons disease (PD). However, since the discovery of its therapeutic potential, no ligand has been successfully developed enough to be tested in the clinic. In the present paper, we report for the first time the medicinal chemistry efforts conducted around the pharmacological tool (-)-PHCCC. This work led to the identification of compound 40, a potent and selective mGluR4 positive allosteric modulator (PAM) with good water solubility and demonstrating consistent activity across validated preclinical rodent models of PD motor symptoms after intraperitoneal administration: haloperidol-induced catalepsy in mouse and the rat 6-hydroxydopamine (6-OHDA) lesion model. Moreover, we also describe the identification of compound 60 a close analogue of compound 40 with improved pharmacokinetic profile after oral administration. On the basis of its favorable and unique preclinical profile, compound 60 (PXT002331, now foliglurax) was nominated as a candidate for clinical development.

Toward the identification of viral cap-methyltransferase inhibitors by fluorescence screening assay

Abstract Two highly pathogenic human coronaviruses associated with severe respiratory syndromes emerged since the beginning of the century. The severe acute respiratory syndrome SARS‐coronavirus (CoV) spread first in southern China in 2003 with about 8000 infected cases in few months. Then in 2012, the Middle East respiratory syndrome (MERS‐CoV) emerged from the Arabian Peninsula giving a still on‐going epidemic associated to a high fatality rate. CoVs are thus considered a major health threat. This is especially true as no vaccine nor specific therapeutic are available against either SARS‐ or MERS‐CoV. Therefore, new drugs need to be identified in order to develop antiviral treatments limiting CoV replication. In this study, we focus on the nsp14 protein, which plays a key role in virus replication as it methylates the RNA cap structure at the N7 position of the guanine. We developed a high‐throughput N7‐MTase assay based on Homogenous Time Resolved Fluorescence (HTRF®) and screened chemical libraries (2000 compounds) on the SARS‐CoV nsp14. 20 compounds inhibiting the SARS‐CoV nsp14 were further evaluated by IC50 determination and their specificity was assessed toward flavivirus‐ and human cap N7‐MTases. Our results reveal three classes of compounds: 1) molecules inhibiting several MTases as well as the dengue virus polymerase activity unspecifically, 2) pan MTases inhibitors targeting both viral and cellular MTases, and 3) inhibitors targeting one viral MTase more specifically showing however activity against the human cap N7‐MTase. These compounds provide a first basis towards the development of more specific inhibitors of viral methyltransferases. HighlightsAn in vitro HTRF assay was set up for methyltransferase (MTase) inhibitors screening.11 inhibitors of SARS‐CoV N7 MTase were identified by screening of a chemical library containing FDA approved drugs.The specificity of SARS‐CoV N7 MTase inhibitors was assessed on others viral and cellular MTases.The highly specific inhibitors may represent a good starting point for the development of antivirals against CoV infection.

Fragment pharmacophore-based in silico screening: a powerful approach for efficient lead discovery

Through a process of fragmentation, functionalization, and recombination of market approved molecules for cosmetic usage, we customized an in-house virtual library comprising molecules ideally suited for virtual screening. Computational pharmacophore-based screening of this virtual library followed by a 3 month optimization phase led to the identification of an optimized lead with all its expected properties in hand to be developed as a candidate molecule for skin care in cosmetic applications. The success of this pilot project paves the way for other cosmetic targets of interest.

Chapter 16 – Ring Transformations

Publisher Summary Noncyclic molecules can be cyclized, attached to, or included in ring systems. In medicinal chemistry three kinds of approaches are currently used. The first approach, the analogical approach, consists of ring-chain transformations, ring contractions or expansions, and various other ring transformations. The second strategy, called the disjunctive approach, aims at the progressive simplification of the original active principle (which is often a natural compound). The objective is to extract information about the minimal structure that is required for activity. Finally, the conjunctive approach is based on the creation or addition of supplementary rings. The objective is to constrain an originally flexible compound and to impose precise conformations and configurations. The preparation of such molecules is of prime importance in the exploration of ligand–receptor interaction and for molecular modeling studies. Molecular variations involving the study of homologous series or the application of the vinylogy concept induce relatively minor changes of the pharmacological profile and result in optimizing the potency. Modifying ring systems—ring-chain transformation, ring contractions and expansions, and reorganization of cyclic systems—represents a highly productive approach in the design of new drug analogs and in the exploration of the drug–receptor interactions.

Chapter 9 – Ring Transformations

Noncyclic molecules can be cyclized, attached to, or included in ring systems. In medicinal chemistry three kinds of approaches are currently used. The first approach, the analogical approach, consists of ring-chain transformations, ring contractions or expansions, and various other ring transformations. The second strategy, called the disjunctive approach, aims at the progressive simplification of the original active principle (which is often a natural compound). The objective is to extract information about the minimal structure that is required for activity. Finally, the conjunctive approach is based on the creation or addition of supplementary rings. The objective is to constrain an originally flexible compound and to impose precise conformations and configurations. The preparation of such molecules is of prime importance in the exploration of ligand -receptor interaction and for molecular modeling studies. Molecular variations involving the study of homologous series or the application of the vinylogy concept induce relatively minor changes of the pharmacological profile and result in optimizing the potency. Modifying ring systems–ring-chain transformation, ring contractions and expansions, and reorganization of cyclic systems–represents a highly productive approach in the design of new drug analogs and in the exploration of the drug-receptor interactions.