Elsevier

Bioorganic & Medicinal Chemistry

Volume 16, Issue 23, 1 December 2008, Pages 10098-10105
Bioorganic & Medicinal Chemistry

Antiobesity designed multiple ligands: Synthesis of pyrazole fatty acid amides and evaluation as hypophagic agents

https://doi.org/10.1016/j.bmc.2008.10.023Get rights and content

Abstract

Searching for new antiobesity agents, a new series of fatty acid amide derivatives of 1,5-diarylpyrazole have been synthesized as dual peroxisome proliferator activated receptor alpha (PPARα)/cannabinoid receptor ligands. The compounds have been evaluated in vivo and in vitro as PPARα activators and as cannabinoids in two tests of the mouse tetrad. In vivo, food intake studies have been performed with all the compounds. No significant cannabinoid activity has been found but some compounds behaved as potent PPARα activators. Several compounds showed anorexigenic properties reducing food intake in rats.

Graphical abstract

Pyrazole fatty acid amides have been synthesized from suitable pyrazole esters, and oleyl and hexadecyl amines. The compounds reduce food intake in rats. The oleyl derivatives are PPARα activators.

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Introduction

Obesity has significantly increased in the last decades affecting an important part of the adult and children population of western countries.1 It is a complex disease involving many physiological signaling systems and different factors, and it is linked to serious health problems.2 Nowadays, only three classes of drug treatments are available, representatives are Orlistat (Xenical)™ a gastrointestinal lipase inhibitor, Sibutramine (Meridia)™ a dual serotonin-norepinephrine reuptake inhibitor, and Rimonabant (Acomplia)™, the first cannabinoid CB1 receptor antagonist approved for clinical use in humans. Although effective in producing weight loss, current therapies against obesity may have some tolerability and/or safety concerns.3 Moreover, since obesity is a complex disease often associated with high cardiovascular risk, type II diabetes and dyslipemia, appetite cannot be considered the only target for medicines designed to fight obesity. Therefore, the development of novel antiobesity drugs is a priority and a challenge for medicinal chemists.

The fact that there are different targets for antiobesity therapy together with a growing interest in multiple ligands4 prompted us to apply this strategy to design potential hypophagic agents capable to target not only appetite, but also lipid and carbohydrate metabolism. Taking in consideration the convergent mechanisms of peroxisome proliferator activated receptors alpha (PPARα) and cannabinoid receptor antagonists as modulators of appetite, lipid metabolism and carbohydrate management by the liver and adipose tissue, we decided to explore a dual cannabinoid/PPARα ligand (Fig. 1). The rationale was to link, in the same molecule, a cannabinoid antagonist motif with a group capable of activating PPARα receptors,5 since the combination of both drugs seems to be additive in terms of controlling appetite.6 The cannabinoid part was the 1,5-diarylpyrazole structure present in Rimonabant and other well established cannabinoid ligands7 and the amide chosen was oleylethanolamide, OEA, a lipid mediator that regulates feeding and lipid metabolism by activating PPARα receptors.8 This idea was further supported by a recent finding in our group in which we have proved that Rimonabant enhances the metabolic benefits of long term treatment with OEA in Zucker rats, a genetic model of obesity, dyslipemia and diabetes due to the lack of leptin signaling.9

Section snippets

Chemistry

The synthetic route used for the preparation of compounds 411 is depicted in Scheme 1 and starts from the 2,4-dicarbonyl esters obtained through condensation of the corresponding ketone and diethyl oxalate in basic medium.10 The pyrazole esters 1a and 1b used for the synthesis of compounds 811 have previously been reported.11, 12 The new pyrazole esters 23 were prepared from ethyl 4-(4-chlorophenyl)-2,4-dioxobutanoate and the corresponding arylhydrazine following the usual procedure.13 In

Biology

The compounds reported in this study were first evaluated for in vitro GST pull down to see which compounds could induce interaction between PPARα and coactivator into MCF-7 cells. The compounds were also screened in the mouse tetrad for cannabinoid activity. Finally, the compounds were evaluated in vivo on food intake and pharmacology studies in rats.

Results and discussion

As can be seen from Figure 2 and Table 1, oleyl derivatives 4, 5, 8 and 9 are capable of activating PPARα receptors, promoting both, its binding to DNA and transcriptional activity. While compound 4 and 8 activated transcription with a similar potency than that of either the reference agonist GW7647 or the endogenous ligand OEA, compounds 5 and 9 were 2–3-fold less potent and the corresponding hexadecyl derivatives 6, 7, 10 and 11 were deprived of PPARα receptor agonist activity. Therefore, it

Conclusions

Dual compounds incorporating cannabinoid and PPARα features in their structure have been synthesized and evaluated. None of the compounds exhibited significant cannabinoid properties. All the chlorophenylpyrazoles bearing oleylamides were capable of activating the PPARα receptors whereas the corresponding hexadecyl derivatives were inactive. Concerning the pyrazole part, the introduction of a methyl at position 4 (as in Rimonabant) does not improve PPARα activity, being the Rimonabant analog 9

General methods

All reagents and solvents were used as commercially received with exception of CH2Cl2 which was distilled from P2O5 prior to use. TLC: precoated silica-gel 60 F254 plates (Merck), detection by UV light (254 nm). Flash-column Chromatography (FC): Kieselgel 60 (230–400 mesh; Merck). Melting points (mp) were determined in open capillaries with a Gallenkamp capillary melting-points apparatus and are uncorrected. 1H and 13C NMR spectra were recorded on Bruker Advance 300 spectrometer operating at

Acknowledgments

This work has been supported by Grants from Proyectos de Excelencia de la Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía, Instituto de Salud Carlos III (FIS PI04/0834, CP04/0039, FIS 07/1226, Redes Temáticas RD06/001), Fundación Eugenio Rodríguez Pascual and Fundació Marató TV3. MCyT, proyectos: MAT2006-01997, SAF2006-13391-C03-02 and “Factoría de Cristalización” Consolider Ingenio 2010. M. Alvarado is also grateful to the Xunta de Galicia (Spain) for a postdoctoral fellowship.

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