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PPARS agonists - Only a few selective PPAR8 agonists have been reported. The phenoxyacid 28 (L-165,041) which is about 600 fold selective for PPARS binding over PPARy, was found to raise HDLc in db/db mice in contrast to the effect of PPARa ligands (70). Another potent and selective PPARS agonist 29 (GW501516) which is 1nM on PPARS and 1000 fold selective over the other subtypes, was shown to increase HDLc in prediabetic obese rhesus monkey by up to 79% (32). The SAR

surrounding the discovery of 29 and the somewhat more selective 30 has recently been published (71).

PPARS/y agonists- While there have been many reports of PPARa/y dual agonists there have been few reports of selective PPAR5/y dual agonists. Generally speaking, achieving PPAR5 selectivity is usually more difficult because of the smaller size of the PPAR8 pocket. One recent report describes the discovery of a PPAR8/y dual agonist 31 from a 480 compound library (72). When dosed in the ZDF rat 31 lowered glucose and trigycerides by about 50% while raising HDLc by 24%.

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