PPARs (Peroxisome proliferator-activated receptors) are ligand-activated transcription factors of nuclear hormone receptor superfamily comprising of the following three subtypes: PPARα, PPARγ, and PPARβ/δ. PPARs play essential roles in the regulation of cellular differentiation, development, and metabolism (carbohydrate, lipid, protein), and tumorigenesis of higher organisms. All PPARs heterodimerize with the retinoid X receptor (RXR) and bind to specific regions on the DNA of target genes. Activation of PPAR-α reduces triglyceride level and is involved in regulation of energy homeostasis. Activation of PPAR-γ enhances glucose metabolism, whereas activation of PPAR-β/δ enhances fatty acids metabolism. Among them, PPARβ/δ is expressed in many tissues, especially in brain, adipose tissue, and skin.

GW0742 (also called GW610742) is a potent and high affinity PPARβ/δ agonist.

GW0742 shows 1000-fold selectivity for PPAR β/δ over the other human subtypes. Meanwhile, GW0742 is also a weak non-steroidal VDR antagonist. GW0742 ameliorates dysfunction in fatty acid oxidation in PSEN1ΔE9 astrocytes. Besides, GW0742 increases astrocytic expression of CPT1A. Similarly, in a mouse model of Alzheimer’s disease (AD), the APP/PS1-mice, GW0742 (oral administration; 30 mg/kg) increases the expression of Cpt1a. In addition, GW0742 concomitantly reverses memory deficits in a fear conditioning test. Furthermore, GW0742 prevented Aβ-induced impairment of long-term potentiation in hippocampal slices.


In Bleomycin instillation in mice, GW0742 (0.3 mg/kg; i.p.) reduces the lung injury and inflammation. Specifically, GW0742 significantly inhibits TNF-α and IL-Iβ levels and significantly reduces the levels of NF-κB p65 in the lung. In contrast, GW0742 decreases the iNOS expression in Bleomycin instillation mice. Moreover, GW0742 reduces the MAPK signalling pathway activation and the following damage to the lung triggered by ERK cascade.

To sum up, GW0742, a potent PPARβ/δ agonist, a VDR antagonist, with anti-inflammatory, antidiabetic and neuroprotective effects.

References:
[1] M Galuppo, et al. Int J Immunopathol Pharmacol. 2010 Oct-Dec;23(4):1033-46.
[2] Henna Konttinen, et al. Glia. 2019 Jan;67(1):146-159.
[3] Kelly A Teske, et al. Bioorg Med Chem Lett. 2018 Feb 1;28(3):351-354.