2. Academic Validation
  3. Design, Synthesis, and Biological Evaluation of Indole Biphenylcarboxylic Acids as PPARγ Antagonists

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

  • ACS Med Chem Lett. 2015 Aug 4;6(9):998-1003. doi: 10.1021/acsmedchemlett.5b00218.
Alice Asteian 1,  Anne-Laure Blayo 1,  Yuanjun He 1,  Marcel Koenig 1,  Youseung Shin 1,  Dana S Kuruvilla 1,  Cesar A Corzo 1,  Michael D Cameron 1,  Li Lin 1,  Claudia Ruiz 1,  Susan Khan 1,  Naresh Kumar 1,  Scott Busby 1,  David P Marciano 1,  Ruben D Garcia-Ordonez 1,  Patrick R Griffin 1,  Theodore M Kamenecka 1
Affiliations

Affiliation

  • 1 Department of Molecular Therapeutics, The Scripps Research Institute, Scripps Florida , 130 Scripps Way #A2A, Jupiter, Florida 33458, United States.
PMID: 26396687 DOI: 10.1021/acsmedchemlett.5b00218
Abstract

The thiazolidinediones (TZD) typified by rosiglitazone are the only approved therapeutics targeting PPARγ 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 PPARγ 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 PPARγ antagonists based on an N-biphenylmethylindole scaffold. Structure-activity relationship studies led to the identification of compound 46 as a high affinity PPARγ Antagonist that exhibits antidiabetic properties following oral administration in diet-induced obese mice.

Keywords

PPARγ; diabetes; indole; nuclear receptor.

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