Design, Synthesis, and Biological Evaluation of Indole Biphenylcarboxylic Acids as PPARγ Antagonists

The thiazolidinediones (TZD) typified by rosiglitazone are the only approved therapeutics targeting PPAR gamma for the treatment of type-2 diabetes (T2DM). Unfortunately, despite robust insulin sensitizing properties, they are accompanied by a number of severe side effects including congestive heart failure, edema, weight gain, and osteoporosis. We recently identified PPAR gamma antagonists that bind reversibly with high affinity but do not induce transactivation of the receptor, yet they act as insulin sensitizers in mouse models of diabetes (SR1664).(1) This Letter details our synthetic exploration around this novel series of PPAR gamma antagonists based on an N-biphenylmethylindole scaffold. Structure-activity relationship studies led to the identification of compound 46 as a high affinity PPAR gamma antagonist that exhibits antidiabetic properties following oral administration in diet-induced obese mice.