Design, synthesis, and evaluation of potent novel peroxisome proliferator-activated receptor gamma indole partial agonists

摘要

Peroxisome Proliferator-Activated Receptor gamma (PPAR gamma) is a nuclear receptor important for glucose homeostasis and insulin sensitivity. The anti-diabetic drugs thiazolidinediones improve insulin sensitivity by blocking PPAR gamma phosphorylation at S273; however, their full agonism on PPAR gamma also causes significant unwanted side effects. The indole derivative UHC1 displays insulin-sensitizing effect by acting as a partial agonist through the inhibition of PPAR gamma S273 phosphorylation, but without full agonist-associated side effects; however, its potency leaves much to be desired. Herein we report the design and synthesis of potent indole analogs as partial PPAR gamma agonists via the structure-activity relationship studies. Our studies revealed that vanillylamine and piperonyl benzylamine at Site 1 are favored to bind PPAR gamma with either biphenyl or 3-trifluoromethyl benzyl group at Site 2. In particular, compound W091A with vanillylamine at Site 1 displays highly potent PPAR gamma binding affinity (IC50 = 16.7 nM), over 30-fold more potent than the parental compound UHC1, yet with less side effect-associated transactivation activity.