The synthesis and structure-activity relationships of novel series of alpha-aryloxyphenylacetic acids as PPARalpha/gamma dual agonists are reported. The initial search for surrogates of the ester group in the screen lead led first to the optimization of a subseries with a ketone moiety. Further efforts to modify the ketone subseries led to the design and synthesis of two new subseries containing fused heterocyclic ring systems. All these analogues were characterized by their "super" PPARalpha agonist activity and weak or partial agonist activity on PPARgamma in PPAR-GAL4 transactivation assays despite their similar binding affinities for both receptors. The cocrystal structures of compounds 7 and rosiglitazone with PPARgamma-LBD were compared, and significant differences were found in their interactions with the receptor. Select analogues in each subseries were further evaluated for in vivo efficacy. They all showed excellent anti-hyperglycemic efficacy in a db/db mouse model and hypolipidemic activity in hamster and dog models without provoking the typical PPARgamma-associated side effects in the rat tolerability assay.

The design and synthesis of a novel class of 2,3-dihydrobenzofuran-2-carboxylic acids as highly potent and subtype-selective PPARalpha agonists are reported. Systematic study of structure-activity relationships has identified several key structural elements within this class for maintaining the potency and subtype selectivity. Select compounds were evaluated in animal models of dyslipidemia using Syrian hamsters and male Beagle dogs, and all these compounds displayed excellent cholesterol- and triglyceride-lowering activity at dose levels that were much lower than the marketed weak PPARalpha agonist fenofibrate.

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Acid Analogues as PPARγ Partial Agonists. -The title compound (IX), prepared via copper--catalyzed boronic acid coupling as synthetic highlight, is evaluated in the db/db mouse model. It causes lowering of glucose at a similar plasma concentration as rosiglitazone. -(DROPINSKI*, J. F.; AKIYAMA, T.; EINSTEIN, M.; HABULIHAZ, B.; DOEBBER, T.; BERGER, J. P.; MEINKE, P. T.; SHI, G. Q.; Bioorg. Med. Chem. Lett. 15 (2005) 22, 5035-5038; Merck Res. Lab., Merck&Co., Inc., Rahway, NJ 07065, USA; Eng.) -C. Oppel