PPARg/y agonists - A large number of PPARa/y dual agonists have been made and put into the clinic. The improved therapeutic profile expected for these dual agonists is the added beneficial effects on serum lipids and diminished weight gain (54). A few TZDs fall in this class but most of the compounds are carboxylic acids. The dual agonist TZDs currently in clinical development are 12 (KRP 297) (55) and 18 (netoglitazone) (56). The alpha-ethoxycarboxylic acid headgroup has been used on many of the earlier PPARy agonists and is also found in 19 (Galida, tesaglitazar, AZ242) currently in phase II clinical trials (57, 58). The crystal structure of this ligand with both the PPARy and PPARa receptors suggests that the carboxylic acid allows binding to both receptors while maintaining the AF2 helix in its activating position, whereas a TZD headgroup could not (58). Compound, 20 (ragaglitazar, NN 622) also a PPARa/y dual agonist with an alpha ethoxy headgroup (59, 60) was recently discontinued in phase III trials because of the incidence of bladder tumors in rodents (61). An extensive SAR study on 20 led to the more potent dual agonist 21 (EC5o PPARa =360nM, PPARy =170nM) where the oxygen of the oxazine has been removed to form a carbazole (62). The tyrosine derivative GW409544 (22). is the most potent PPARa/y described to date with a PPARa EC50 of 2nM and a PPARy EC50 of 0.2nM (38). A clever modification of the tyrosine motif that incorporates the nitrogen into the sidechain thus eliminating the stereogenic center produced 23 (BMS 298585) which is twice as potent on PPARy as PPARa (EC50 = 120 and 240nM respectively) in the cellular transfection assay. It is reported to lower glucose in the db/db mouse model with a beneficial effect on plasma lipids without weight gain (63-65). Compound 24 (LY 465608) (66, 67) is composed of a fibrate headgroup and oxazole tail that is similar to many of the PPARy agonists [Note: This compound was previously incorrectly identified as LY 519818 (structure unknown)] (2). It is six times more potent on PPARa than on PPARy (EC50 =150 and 880nM respectively). Treatment of apoE knockout mice with 24 resulted in a 2.5-fold reduction in aortic atherosclerotic lesion (68). The SAR on a series based on BVT.142 (25) showed that replacement of the R group could enhance the PPARy selectivity form 6:1 for 25 to >300:1 for 27. The x-ray structure of 26 showed that the key interactions with the AF2 helix found with most other PPARy agonists was missing. This might explain the lower potency for this series (EC50S PPARy =300-1600nM and PPARa = 2500->10000nM) (69).
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