Chimie thérapeutique

L’objectif de cette thématique est de découvrir et développer de petits ligands de récepteurs d’intérêt par des approches de criblage et/ou de stratégies classiques de « drug design » pour des applications mécanistique et/ou thérapeutique.

Nous nous intéressons à trois cibles thérapeutiques : le récepteur de l’Apeline et ses implications en cardiovasculaire, le récepteur de l’ocytocine et son implication dans les phénomènes d’attachement et les troubles du comportement (Autisme) et enfin les Chimiokines et leur implication dans les maladies inflammatoires (Asthme).

Apeline et cardiovasculaire

Development of Original Metabolically Stable Apelin-17 Analogs with Diuretic and Cardiovascular Effects.

FASEB J., 2016, doi:10.1096/fj.201600784R.

Apelin, a (neuro)vasoactive peptide, plays a prominent role in controlling cardiovascular functions and water balance. Since the in vivo apelin half-life is in the min range, we aimed to identify metabolically stable apelin 17 (K17F) analogs. We generated P92 by classical chemical substitutions, and LIT01-196 by the original addition of a fluorocarbon chain to the N-terminus of K17F. Both were much more stable in plasma (half-life > 24 h for LIT01-196) than K17F (4.6 min). Given intravenously (nmol/kg range) in normotensive rats, these analogs potently increased urine output and induced a profound and sustained decrease in arterial blood pressure. In conclusion, these new compounds, which favour diuresis and improve cardiac contractility whilst reducing vascular resistances, represent promising candidates for the treatment of heart failure, water retention/hyponatremic disorders.

Structure–Activity Relationship Studies toward the Discovery of Selective Apelin Receptor Agonists

 J. Med. Chem. 2014, 7, 2908-2919.

Apelin is the endogenous ligand for the previously orphan G protein-coupled receptor APJ. Apelin and its receptor are widely distributed in the brain, heart and vasculature, and are emerging as an important regulator of body fluid homeostasis and cardiovascular functions. To further progress in the pharmacology and the physiological role of the apelin receptor, the development of small, bioavailable agonists and antagonists of the apelin receptor, is crucial. In this context, E339-3D6 (27) was described as the first non-peptidic apelin receptor agonist. The study of the structure-activity relationships led to the identification of ligands 19, 21 and 38, which display an increased affinity compared to 27. The latter and 19 behave as full agonists with regard to cAMP production and apelin receptor internalization whereas 21 is a biased agonist towards cAMP production. Interestingly, the three ligands display a much higher stability in mouse plasma (T_1/2 > 10 h) than the endogenous apelin-17 peptide 2 (T_1/2 < 4 min).

Identification and pharmacological properties of E339-3D6, the first nonpeptidic apelin receptor agonist

FASEB J., 2010, 24, 1506-1517.

Apelin plays a prominent role in body fluid and cardiovascular homeostasis. To explore further upstream the role played by this peptide, non-peptidic agonists and antagonists of the apelin receptor are required. To identify such compounds which do not exist to date, we used an original Fluorescence Resonance Energy Transfer-based assay to screen a GPCR-focused library of fluorescent compounds on the human EGFP-tagged apelin receptor. This led to isolate E339-3D6 that displayed a 90 nmol/L affinity, behaved as a partial agonist with regard to cAMP production and as a full agonist with regard to apelin receptor internalization. Finally, E339-3D6 induced vasorelaxation of rat aorta precontracted with noradrenaline and potently inhibited systemic vasopressin release in water-deprived mice when intracerebroventricularly injected. This compound represents the first non-peptidic agonist of the apelin receptor, the optimization of which will allow to develop a new generation of vasodilator and aquaretic agents.

Ocytocine et autisme/attachement

LIT-001, the First Nonpeptide Oxytocin Receptor Agonist that Improves Social Interaction in a Mouse Model of Autism

J. Med. Chem., 2018, 61, 8670-8692

Oxytocin (OT) and its receptor (OT-R) are implicated in the etiology of autism spectrum disorders (ASD), and OT-R is a potential target for therapeutic intervention. Very few nonpeptide oxytocin agonists have currently been reported. Their molecular and in vivo pharmacology remain to be clarified, and none of them has been shown to be efficient in improving social interaction in animal models relevant to ASD. In an attempt to rationalize the design of centrally active nonpeptide full agonists, we studied in a systematic way the structural determinants of the affinity and efficacy of representative ligands of the V_1a and V₂ vasopressin receptor subtypes (V_1a-R and V₂-R) and of the oxytocin receptor. Our results confirm the subtlety of the structure–affinity and structure–efficacy relationships around vasopressin/oxytocin receptor ligands and lead however to the first nonpeptide OT receptor agonist active in a mouse model of ASD after peripheral ip administration.

Subtlety of the Structure−Affinity and Structure−Efficacy Relationships around a Nonpeptide Oxytocin Receptor Agonist

J. Med. Chem., 2010, 53, 1546–1562

Very few nonpeptide oxytocin agonists have currently been reported, and none of them seem suitable for the in vivo investigation of the oxytocin mediated functions. In an attempt to rationalize the design of better tools, we have systematically studied the structural determinants of the affinity and efficacy of representative ligands of the V_1a, V₂, and OT receptor subtypes. Despite apparently obvious similarity between the ligand structures on one hand, and between the receptor subtypes on the other hand, the binding affinity and the functional activity profiles of truncated and hybrid ligands highlight the subtlety of ligand−receptor interactions for obtaining nonpeptide OT receptor agonists.

Chimiokines et inflammation

Discovery of a Locally and Orally Active CXCL12 Neutraligand (LIT-927) with Anti-inflammatory Effect in a Murine Model of Allergic Airway Hypereosinophilia

J. Med. Chem., 2018, 61, 7671-7686

We previously reported Chalcone-4 (1) that binds the chemokine CXCL12, not its cognate receptors CXCR4 or CXCR7, and neutralizes its biological activity. However, this neutraligand suffers from limitations such as poor chemical stability, solubility, and oral activity. Herein, we report on the discovery of pyrimidinone 57 (LIT-927), a novel neutraligand of CXCL12 which displays a higher solubility than 1 and is no longer a Michael acceptor. While both 1 and 57 reduce eosinophil recruitment in a murine model of allergic airway hypereosinophilia, 57 is the only one to display inhibitory activity following oral administration. Thereby, we here describe 57 as the first orally active CXCL12 neutraligand with anti-inflammatory properties. Combined with a high binding selectivity for CXCL12 over other chemokines, 57 represents a powerful pharmacological tool to investigate CXCL12 physiology in vivo and to explore the activity of chemokine neutralization in inflammatory and related diseases.

An antedrug of the CXCL12 neutraligand blocks experimental allergic asthma without systemic effect in the mouse

J. Biol. Chem., 2013, 17, 11865-11876.

The chemokine receptor CXCR4 and its chemokine CXCL12 are involved in normal tissue patterning, but also in tumor cell growth and survival as well as in the recruitment of immune and inflammatory cells, as successfully demonstrated using agents that block either CXCL12 or CXCR4. In order to achieve selectivity in drug action on the CXCR4/CXCL12 pair in particular in the airways, drugs should be delivered as selectively as possible in the treated tissue, and should not diffuse in the systemic circulation where it may reach undesired organs. To this end, we used a previously unexploited Knoevenagel reaction to create a short-lived drug, or soft drug, based on the CXCL12-neutralizing small molecule, chalcone 4, which blocks binding of CXCL12 to CXCR4. We show that the compound, carbonitrile-chalcone 4, blocks the recruitment of eosinophils to the airways in ovalbumin-sensitized and challenged mice in vivo when administered directly to the airways by intranasal route, but not when administered systemically by intraperitoneal route. We show that the lack of effect at a distant site is due to the rapid degradation of the molecule to inactive fragments. This approach allows selective action of the CXCL12 neutraligands even though the target protein is widely distributed in the organism.

Prodrugs of a CXC Chemokine-12 (CXCL12) Neutraligand Prevent Inflammatory Reactions in an Asthma Model in Vivo

ACS Med. Chem. Lett., 2012, 3, 10-14.

Chalcone 4 (1) is a small molecule that neutralizes the CXC chemokine CXCL12 and prevents it from acting on the CXCR4 and CXCR7 receptors. To overcome its poor solubility in aqueous buffers, we designed highly soluble analogues of compound 1, one phosphate (Prodrug 2), one l-seryl and one sulfate, all inactive by themselves on CXCL12 but when cleaved in vivo into 1, highly active locally at a low dose in a mouse airway hypereosinophilia model.

Small Neutralizing Molecules to Inhibit Actions of the Chemokine CXCL12

J. Biol. Chem., 2008, 283, 23189-23199

The chemokine CXCL12 and the receptor CXCR4 play pivotal roles in normal vascular and neuronal development, in inflammatory responses, and in infectious diseases and cancer. For instance, CXCL12 has been shown to mediate human immunodeficiency virus-induced neurotoxicity, proliferative retinopathy and chronic inflammation, whereas its receptor CXCR4 is involved in human immunodeficiency virus infection, cancer metastasis and in the rare disease known as the warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis (WHIM) syndrome. As we screened chemical libraries to find inhibitors of the interaction between CXCL12 and the receptor CXCR4, we identified synthetic compounds from the family of chalcones that reduce binding of CXCL12 to CXCR4, inhibit calcium responses mediated by the receptor, and prevent CXCR4 internalization in response to CXCL12. We found that the chemical compounds display an original mechanism of action as they bind to the chemokine but not to CXCR4. The highest affinity molecule blocked chemotaxis of human peripheral blood lymphocytes ex vivo. It was also active in vivo in a mouse model of allergic eosinophilic airway inflammation in which we detected inhibition of the inflammatory infiltrate. The compound showed selectivity for CXCL12 and not for CCL5 and CXCL8 chemokines and blocked CXCL12 binding to its second receptor, CXCR7. By analogy to the effect of neutralizing antibodies, this molecule behaves as a small organic neutralizing compound that may prove to have valuable pharmacological and therapeutic potential.