Régis Millet

Recent Advances in the Development of Selective CB2 Agonists as Promising Anti-Inflammatory Agents

The high distribution of CB(2) receptors in immune cells suggests their important role in the control of inflammation. Growing evidence offers this receptor as an attractive therapeutic target: CB(2) selective agonists are able to modulate inflammation without triggering psychotropic effects. This review will summarize the literature on the implication of CB(2) in inflammation and CB(2) selective agonists with anti-inflammatory activity.

Novel potent substance P and neurokinin A receptor antagonists. Conception, synthesis and biological evaluation of indolizine derivatives.

Exploration of SAR around dual NK(1)/NK(2) antagonist Cbz-Gly-Leu-Trp-OBzl(CF(3))(2) and its derivatives disclosed the essential requirements for more potent dual NK(1)/NK(2) binding. We report here the synthesis and the biological properties of a novel series of indolizine including pharmacophoric elements.

Synthesis of an azabicycloalkane amino acid scaffold as potential rigid dipeptide mimetic

Abstract Short syntheses are presented of the pseudo-dipeptide (3 S ,6 S )-6-[(benzyloxy)carbonyl]amino-5-oxo-1,2,3,5,6,7-hexahydro-3-indolizinecarboxylic acid ( 1a ) and of its (3 S ,6 R ) diastereoisomer ( 1b ). The key step involves adding vinylogous β-enaminoester derived from pyroglutamic acid on an acrylate derivative. The 6,5-fused bicyclic lactam obtained may be viewed as a conformationally restricted Ala-Pro mimetic.

Antitrypanosomal activities and cytotoxicity of 5-nitro-2-furancarbohydrazides

A series of 5-nitro-2-furancarbohydrazides were synthesized. In vitro antitrypanosomal activities of these compounds were determined against the closely related protozoa Trypanosoma cruzi Trypanosoma brucei and discussed in relation to potential targets.

Synthesis and biological evaluation of conformationally restricted derivatives of tryptophan as NK1/NK2 ligands

Chemical modifications on the NK1 competitive antagonist L-732,138, with a view to creating a dual NK1/NK2 ligand, led to the tryptophan derivative 1 possessing the protected Gly-Leu sequence of the C-terminus of substance P and neurokinin A. Modifications in the nature of the carbamate function increased the selectivity for the NK1 receptor, whereas the inclusion of the indole moiety in β-carboline or carbazole rings decreased the affinity for both receptors. Free indolylmethyl and Cbz carbamate groups were shown to be essential for NK2 affinity.

Scaffold hopping strategy toward original pyrazolines as selective CB2 receptor ligands

In line of a scaffold hopping strategy of pyrazole structures, especially known as potent CB(2) receptor antagonists, we exploited an original and convergent synthesis of a new class of C4-benzyl pyrazolines and derivatives from readily available hydrazones and enones (two or three steps). Making use of a mixture of resin supported reagents strategy an efficient domino process allowed the easy construction of various dihydropyrazoles in 63-83% yields. The obtained family of pyrazolines featured significant hCB(2)/hCB(1) selectivity in favor of hCB(2) receptors while more than 1000-3000 nM affinity was only measured for hCB(1) receptors. This is closely related to pyrazole SR144528 inverse agonist/antagonist, although a partial agonist behavior in the [(35)S]-GTPγS binding assay was mainly measured in our case pointing out a functional switch in action. Furthermore, this hCB(2) selectivity is unique within the pyrazoline CB ligands although the affinity ranging from 251 to 689 nM remains to be improved which give, however, an opportunity for further structure-activity relationship.

A flexible approach to the design of new potent substance P receptor ligands

The development of small‐molecule antagonists of the substance‐P‐preferring tachykinin NK1 receptor offers an excellent opportunity to exploit these molecules as novel therapeutic agents in diverse pathologies such as depression, emesis or asthma. GR71251 has previously been identified as a potent and selective substance‐P‐receptor antagonist. We have therefore undertaken the synthesis of new pseudopeptidic analogues based on the C‐terminal sequence of GR71251. The evaluation of binding affinities toward NK1 and NK2 receptors has enabled us to propose new selective NK1 ligands with high affinity. Structure‐activity relationships showed that the Trp‐OBzl(CF3)2 moiety is essential for NK1 affinity and that the introduction of building units such as spirolactam, lactam or proline, leading to a constrained peptide, increased selectivity for NK1 receptors. These compounds constitute a useful starting point for new substance P antagonists and represent an attractive lead series for further studies on the design of specific NK1 antagonists.

Synthesis and biological evaluation of tripeptide derivatives of Cbz-Gly-Leu-Trp-OBzl(CF3)2 as NK1/NK2 ligands

Chemical modifications were obtained on the dual NK1/NK2 ligand Cbz-Gly-Leu-Trp-OBzl(CF3)2 with a view to optimizing affinities for both NK1 and NK2 receptors. Replacement of the Gly residue by other amino acids increased affinities for NK1/NK2 receptors or induced selectivity for the NK1 receptor.

On the synthesis and biological properties of isocombretastatins: a case of ketone homologation during Wittig reaction attempts

New isocombretastatins were synthesized by reacting the corresponding phenstatin analogs with CH3PPh3Br in presence of tBuOK. These new derivatives showed significant activities against cellular proliferation and tubulin polymerization. In particular, monomethoxylated derivatives of phenstatin and isoCA-4 exhibit similar activities to those of parent phenstatin. Attempts of the Wittig reaction on 2- (or 4-) methoxy-4′-nitrobenzophenones in the same conditions do not lead to the expected isocombretastatins but to methyleneketones with the exclusion of triphenylphosphine. A mechanism for this new ketone homologation was proposed.

New substance P receptor antagonists. Conception, synthesis and biological evaluation of spirolactam derivatives and their tripeptide Cbz-Pro-Leu-Trp-OBzl(CF3)2 and lactam pseudopeptide derivatives

New chemical entities were designed from the C-terminal sequence of GR71251, an NK1 pseudopeptide antagonist. Three new NK1 antagonists were identified with high affinity and selectivity for NK1 receptors.