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PPAR pan agonists - In recently published studies, selective PPAR agonists were dosed in combination to show that some synergy could be achieved with respect to glucose lowering and effects on lipids (73-75). This study demonstrated that nonselective or PPAR pan agonists might be useful therapeutics. The pan agonist oxadiazole 32 was found to be 320nM against PPAR5 and 10-fold more potent on the PPARa and PPARy receptors in the cellular transfection assay. Most of the PPARa and PPARy activity resides in the (-) isomer, which is presumed to have the (S) configuration as depicted, while the PPAR8 activity is similar for both enantiomers (76). The benzofuran 33, also a pan agonist in the low nanomolar range, lowered glucose levels in a db/db mouse model by 77% but was less effective in the ZDF rat model (27% glucose lowering) (77). A structurally related series of benzisoxazoles derived from meta substituted phenyl acetic acids yielded the potent pan agonist 34, which at a dose of 10mg/kg effectively lowered glucose in the db/db mouse. Since 34 did not bind the mouse PPARa receptor the in vivo results only reflect a PPARy effect (78). A series of alpha ethoxy acids that were conceptually derived from 20 by removal of the oxygen in the oxazine moiety and exchanging the N along with its adjacent C with a double bond yielded a series of PPAR pan agonists the most potent depicted as 35. Compound 36, about 3-fold more potent on PPARy and 3-fold less potent on PPARa than 35, was tested in the db/db mouse and found to be as effective as 20, lowering the AUC in the OGTT by 52% (79).

PPAR modulators - Some PPAR ligands bind to the receptor well but only elicit a partial response in the functional transfection assay. These compounds are called partial agonists, modulators or antagonists depending on how they are characterized. The partial PPARy agonist 37 is potent against PPARy (EC5o=57nM) in the cellular transfection assay but only reaches about 25% of the maximum response of the standard rosiglitazone (80, 81). It is also a partial agonist in the adipocyte differentiation assay, inducing the expression of adipose fatty acid binding protein (aP2) mRNA to only 40% in 3T3-L1 cells. Interestingly, 37 ameliorated hyperglycemia and hyperinsulinemia in fat-fed C57BL/6J mice without weight gain and cardiac hypertrophy that is characteristic of the TZD full agonists. Sulphonamides 38 and 39 are among the preferred compounds in a recent Tularik patent covering PPARy modulators (82). While 37, 38 and 39 all have acidic groups it is difficult to see how they might bind in the receptor like TZDs. The different binding mode might well be responsible for the partial agonist activity. The three similar 2-chloro-5-nitro-N-benzamide derivatives 41 (GW9662) (83), 42 (T0070907) (84) and 43 (85) are all reported to be PPARy antagonists as shown by binding and transfection experiments. These compounds also inhibit adipocyte differentiation in vitro. Both 41 and 42 have been shown to irreversibly covalently modify Cys285 in helix 3 of the PPARy LBD. While this cysteine is conserved in PPARa and PPAR5 the irreversible binding with these subtypes is not significant on the time scale of most of the experiments.

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