Antiobesity designed multiple ligands: Synthesis of pyrazole fatty acid amides and evaluation as hypophagic agents
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.
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 4–11 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 8–11 have previously been reported.11, 12 The new pyrazole esters 2–3 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.
References and notes (24)
- et al.
Lancet
(2007) - et al.
Neuropharmacology
(2008) - et al.
EMBO J.
(1996) - et al.
Nature
(2001) J. Med. Chem.
(2006)J. Med. Chem.
(2006)- et al.
J. Med. Chem.
(2006) - Alvarado, M.; Goya, P.; Jagerovic, N.; Elguero, J.; Macías-González, M.; Serrano A.; Rodríguez de Fonseca, F. Patent...
- et al.
J. Neurosci.
(2002) - et al.
Curr. Top. Med. Chem.
(2008)
Nature
J. Org. Chem.
Org. Proc. Res. Dev.
Cited by (37)
Synthesis and Antimicrobial Screening of 3-Fluoromethyl Pyrazole Derivatives
2023, Polycyclic Aromatic CompoundsSynthesis, molecular docking, and in-vivo anti-inflammatory screening of novel substituted pyrazole analogues
2022, Journal of Molecular StructureCitation Excerpt :The pyrazole, an important heterocyclic group is present in Celecoxib, which is a di-aryl pyrazole derivative [1]. The pyrazole derivatives are well known for various activities like anticonvulsant [2], antidepressant [3], anti-inflammatory [4,5], antimicrobial [6], analgesic [7], anticancer [8], antihypertensive [9], antiobesity [10], antiviral [11], hypoglycaemia [12], leishmanicidal [13] and antituberculosis [14] activities. In this present work, we tried to incorporate the diaryl pyrazole moiety into the thiazole moiety and to explore the possible increase in the activity, because of the incorporation of two heterocyclic moieties.
Anti-hyperlipidemic potential of natural product based labdane-pyrroles via inhibition of cholesterol and triglycerides synthesis
2021, Bioorganic ChemistryCitation Excerpt :As depicted in Fig. 1, labdane terpenes, pyrroles, and pyrazole constitute a crucial central core in many of the FDA approved statin drugs [11–14]. Besides, pyrrole and pyrazole represent as a vital scaffold in medicinal chemistry with their diverse pharmacological properties [36–39]. Therefore, we emphasize that the molecular hybridization of these pharmacophores in single entity will enrich the pharmacological properties in finding the potent “leads” as Anti-hyperlipidemic agents.
The Chemistry of Acetylpyrazoles and Its Utility in Heterocyclic Synthesis
2019, Journal of Heterocyclic ChemistrySynthesis and biological evaluation of pyrazole linked benzothiazole-β-naphthol derivatives as topoisomerase I inhibitors with DNA binding ability
2019, Bioorganic and Medicinal ChemistryCitation Excerpt :2,5-dibenzothiazolyl furans (III and IV, Fig. 1) are active against different human cancer cell lines including MCF-7 and HeLa exhibiting good DNA minor groove interactions.19 Considering the mechanism of action, benzothiazoles can act as inhibitors of tyrosine kinase, selective HIV type-1 transcriptase20 and topoisomerases I and II. Whereas beta-naphthol moieties also possess tremendous applications in synthetic and medicinal chemistry.