Design and Synthesis of PPAR ligands

This work describes the design and synthesis of proposed antagonists of PPARalpha/gammaproteins. Preliminary work by collaborators indicated both subtypes may influence development of mesothelioma, a universally fatal asbestos-induced tumour. Transcriptome analysis indicated that both subtypes were overactive in mesothelial tumour cell lines, leading to the initial hypothesis that inhibition of PPARalpha/gamma could be useful in treating mesothelioma; thus, dual PPARa/gantagonists were desired as probes. Proposed antagonists were designed by applying molecular extension to reported dual PPARalpha/gamma agonists, then synthesised and tested iteratively. Target validation studies revealed that PPARg-selective inhibitors were of greater interest.