Aline Moulin

Synthesis of 3,4,5-Trisubstituted-1,2,4-triazoles

Triazoles are an important class of heterocyclic compounds not only as a core scaffold but also as a benzo-fused (triazolopyridines and triazolopyrazines are well-known examples) or functionalized one, such as alkylthiotriazoles. Indeed, the number of patents describing this attractive heterocycle (excluding benzo-fused compounds) with interesting biological properties is increasingly growing (Figure 1). Furthermore, among those patents, the 3,4,5-trisubstituted 1,2,4-triazole scaffold is clearly tending to become the most claimed. It displays in fact a wide range of biological activities and can be used as amide bond isostere for the design of receptor ligands in order to enhance their pharmacokinetic properties.1,2 Some pseudopeptide modifications (tetrazole,3 for example) mimicking the cis amide bond orientation have been shown to introduce a very useful orientation of side chains. The biological activities of these pseudopeptides allowed considering that in some cases the active conformation of the peptide bond could be cis and not trans. 1,2,4-triazoles * To whom correspondence should be addressed. E-mail: jean-alain.fehrentz@ univ-montp1.fr. † Present address: Flamel Technologies, Parc Club du Moulin à Vent, 33 avenue du Docteur Georges Lévy, 69693 Vénissieux, France. Aline Moulin was born in Guilherand-Granges-lès-Valence (Ardèche), France, in 1981. She was awarded by the National Graduate Chemistry School of Montpellier in Organic Chemistry and received her M.Sc. degree in Biomolecular Chemistry from the University Montpellier II in 2004. She then achieved her Ph.D. studies under the supervision of Dr. Jean-Alain Fehrentz at the Institut des Biomolécules Max Mousseron in Montpellier. She was appointed Research Scientist in Medicinal Chemistry in 2007 at Sanofi-Aventis Research Center (Vitry-sur-Seine, France), where she worked on the development of CNS targeting heterocyclic scaffolds. She then joined Flamel Technologies chemistry research and development team (Venissieux, France) in 2009 to work on the design of drug delivery systems. Her research interests are focused on the design and synthesis of bioactive compounds.

Anorexigenic and electrophysiological actions of novel ghrelin receptor (GHS-R1A) antagonists in rats.

Here we provide the first pharmacological exploration of the impact of acute central nervous system exposure to three recently developed ghrelin receptor (GHS-R1A) ligands on food intake and on the electrical activity of the target cells for ghrelin in the hypothalamus. Central (i.c.v) injection of GHS-R1A antagonists to rats suppressed food intake induced by i.c.v ghrelin injection (1 microg) in a dose-dependent manner with a total blockade at concentrations of 0.4 microg and 8 microg for JMV 3002 and JMV 2959 respectively. JMV 2810, a partial agonist, also suppressed ghrelin-induced food intake (range: 0.02-2 microg). Moreover all three compounds reduced fasting-induced food intake in rats (i.e. the amount of food eaten during the first hour of food exposure after a 16 h fast). At the single cell level we also explored the effects of the compounds to suppress ghrelin (0.5 microM)-induced changes in electrical activity of arcuate nucleus cells recorded extracellularly in a slice preparation. Preincubation followed by perfusion with the GHS-R1A ligands suppressed the responsiveness of arcuate cells to ghrelin. Thus, the recently developed GHS-R1A ligands (JMV 3002, 2959 and 2810) suppress ghrelin-induced and fasting-induced food intake at the level of the central nervous system. This appears to be mediated, at least in part, by a modulation of the activity of ghrelin-responsive arcuate nucleus cells. As the central ghrelin signalling system has emerged as an important pro-obesity target, it will be important to establish the efficacy of these GHS-R1A ligands to reduce fat mass in clinical studies.

New trisubstituted 1,2,4-triazole derivatives as potent ghrelin receptor antagonists. 3. Synthesis and pharmacological in vitro and in vivo evaluations.

Ghrelin receptor ligands based on trisubstituted 1,2,4-triazole structure were synthesized and evaluated for their in vitro binding and biological activity. In this study, we explored the replacement of the alpha-aminoisobutyryl moiety by aromatic or heteroaromatic groups. Compounds 5 and 34 acted as potent in vivo antagonists of hexarelin-stimulated food intake. These two compounds did not stimulate growth hormone secretion in rodents and did not antagonize growth hormone secretion induced by hexarelin.

Recent developments in ghrelin receptor ligands.

The 28‐amino acid peptide ghrelin is a neuroendocrine hormone synthesized primarily in the stomach. It stimulates growth hormone secretion and appetite, thus promoting food intake and body‐weight gain. The pharmacological properties of this peptide are mediated by the growth hormone secretagogue receptor type 1a (GHS‐R1a). Given its wide spectrum of biological activities, it is evident that the discovery of ghrelin and its receptor has opened up many perspectives in the fields of neuroendocrine and metabolic research and has had an influence on such fields of internal medicine as gastroenterology, oncology, and cardiology. It is therefore increasingly likely that synthetic, peptidyl, and nonpeptidyl GHS‐R1a ligands, acting as agonists, partial agonists, antagonists, or inverse agonists, could have both clinical and therapeutic potential. This review summarizes the various types of GHS‐R1a ligands that have been described in the literature and discusses the recent progress made in this research area.