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

Bioorg Med Chem Lett. 2019 Nov 15;29(22):126664. doi: 10.1016/j.bmcl.2019.126664. Epub 2019 Sep 3.

Abstract

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

Keywords: Diabetes; Insulin resistance; Obesity; PPARγ; PPARγ agonist; Partial agonist; TZD.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Dose-Response Relationship, Drug
  • Drug Design*
  • Hypoglycemic Agents / chemical synthesis
  • Hypoglycemic Agents / chemistry
  • Hypoglycemic Agents / pharmacology*
  • Indoles / chemical synthesis
  • Indoles / chemistry
  • Indoles / pharmacology*
  • Models, Molecular
  • Molecular Structure
  • PPAR gamma / agonists*
  • Structure-Activity Relationship

Substances

  • Hypoglycemic Agents
  • Indoles
  • PPAR gamma