Identification of a subtype selective human PPARα agonist through parallel-array synthesis

doi:10.1016/S0960-894X(01)00188-3

Bioorganic & Medicinal Chemistry Letters

Volume 11, Issue 9, 7 May 2001, Pages 1225-1227

https://doi.org/10.1016/S0960-894X(01)00188-3 Get rights and content

Abstract

Using solid-phase, parallel-array synthesis, a series of urea-substituted thioisobutyric acids was synthesized and assayed for activity on the human PPAR subtypes. GW7647 (3) was identified as a potent human PPARα agonist with ∼200-fold selectivity over PPARγ and PPARδ, and potent lipid-lowering activity in animal models of dyslipidemia. GW7647 (3) will be a valuable chemical tool for studying the biology of PPARα in human cells and animal models of disease.

Using solid-phase, parallel-array synthesis, a series of urea-substituted thioisobutyric acids was synthesized. GW7647 (3) was identified as a potent, selective human PPARα agonist.

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Citation Excerpt :
This finding may be a reflection of the selectivity of GW7647. GW7647 is ∼200-fold selective for murine PPARα (EC50 = 0.001 μM for PPARα; EC50 = 1.3 μM for PPARγ; EC50 = 2.91 μM for PPARδ; Brown et al., 2001). The intra-VP anti-nausea effect of GW7647 is consistent with previous data from our group showing that systemic GW7647 (3 mg/kg, i.p.) reduced LiCl-induced gaping, without producing conditioned gaping on its own (Rock et al., 2017).
Here we investigate the involvement of the ventral pallidum (VP) in the anti-nausea effect of fatty acid amide hydrolase (FAAH) inhibition with PF-3845, and examine the pharmacological mechanism of such an effect. We explored the potential of intra-VP PF-3845 to reduce the establishment of lithium chloride (LiCl)-induced conditioned gaping (a model of acute nausea) in male Sprague-Dawley rats. As well, the role of the cannabinoid 1 (CB₁) receptors and the peroxisome proliferator-activated receptors-α (PPARα) in the anti-nausea effect of PF-3845 was examined. Finally, the potential of intra-VP GW7647, a PPARα agonist, to reduce acute nausea was also evaluated. Intra-VP PF-3845 dose-dependently reduced acute nausea by a PPARα mechanism (and not a CB₁ receptor mechanism). Intra-VP administration of GW7647, similarly attenuated acute nausea. These findings suggest that the anti-nausea action of FAAH inhibition may occur in the VP, and may involve activation of PPARα to suppress acute nausea.

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Identification of a subtype selective human PPARα agonist through parallel-array synthesis

Abstract

Chem. Biol.

Prog. Lipid Res.

J. Med. Chem.

Nature