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

ABSTRACT: Peroxisome Proliferator-Activated Receptor ? (PPAR?) is a nuclear receptor important for glucose homeostasis and insulin sensitivity. The anti-diabetic drugs thiazolidinediones improve insulin sensitivity by blocking PPAR? phosphorylation at S273; however, their full agonism on PPAR? 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? 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? agonists via the structure-activity relationship studies. Our studies revealed that vanillylamine and piperonyl benzylamine at Site 1 are favored to bind PPAR? with either biphenyl or 3-trifluoromethyl benzyl group at Site 2. In particular, compound WO91A with vanillylamine at Site 1 displays highly potent PPAR? binding affinity (IC50?=?16.7?nM), over 30-fold more potent than the parental compound UHC1, yet with less side effect-associated transactivation activity.

SUBMITTER: Eeda V 

PROVIDER: S-EPMC7243741 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature