Effect of Oxime Ether Incorporation in Acyl Indole Derivatives on PPAR Subtype Selectivity

Compounds that simultaneously activate peroxisome proliferator-activated receptor (PPAR) subtypes alpha and gamma have the potential to effectively treat dyslipidemia and type 2 diabetes (T2D) in a single pharmaceutically active molecule. The frequently observed side effects of selective PPAR gamma agonists, such as edema and weight gain, were expected to be overcome by using additive PPAR alpha activity, leading to dual PPAR alpha/gamma agonists with balanced activity for both subtypes. Herein we report the discovery, synthesis, and optimization of a new series of alpha-ethoxyphenylpropionic acid bearing 5- or 6-substituted in-doles. The incorporation of oxime ethers on the carbonyl portion of the benzoyl group can bring the PPAR alpha/gamma potency ratio equal to or slightly greater than one, as is the case for compounds 20c and 21a. Compound 20c shows high efficacy in an ob/ob mouse model of T2D and dyslipidemia, similar to that of rosiglitazone and tesaglitazar, but with a significant increase in body weight gain. In contrast, compound 21a, less potent as a dual PPAR alpha/gamma activator than 20c, showed an interesting pharmacological profile, as it elicits a decrease in body weight relative to reference compounds.