2. Academic Validation
  3. 7-Methylation of Chenodeoxycholic Acid Derivatives Yields a Substantial Increase in TGR5 Receptor Potency

7-Methylation of Chenodeoxycholic Acid Derivatives Yields a Substantial Increase in TGR5 Receptor Potency

  • J Med Chem. 2019 Jul 25;62(14):6824-6830. doi: 10.1021/acs.jmedchem.9b00770.
Ali Nakhi 1,  Connor M McDermott 2,  Kristen L Stoltz 1,  Kristen John 1,  Jon E Hawkinson 1,  Elizabeth A Ambrose 2,  Alexander Khoruts 3 4,  Michael J Sadowsky 4,  Peter I Dosa 1
Affiliations

Affiliations

  • 1 Institute for Therapeutics Discovery and Development, Department of Medicinal Chemistry , University of Minnesota , 717 Delaware Street SE , Minneapolis , Minnesota 55414 , United States.
  • 2 Department of Medicinal Chemistry , University of Minnesota , 717 Delaware Street SE , Minneapolis , Minnesota 55414 , United States.
  • 3 Center for Immunology, Department of Medicine, Division of Gastroenterology , University of Minnesota , Minneapolis , Minnesota 55414 , United States.
  • 4 BioTechnology Institute, Department of Soil, Water & Climate, and Department of Plant and Microbial Biology , University of Minnesota , St. Paul , Minnesota 55108 , United States.
PMID: 31268316 DOI: 10.1021/acs.jmedchem.9b00770
Abstract

TGR5 agonists are potential therapeutics for a variety of conditions including type 2 diabetes, obesity, and inflammatory bowel disease. After screening a library of chenodeoxycholic acid (CDCA) derivatives, it was determined that a range of modifications could be made to the acid moiety of CDCA which significantly increased TGR5 agonist potency. Surprisingly, methylation of the 7-hydroxyl of CDCA led to a further dramatic increase in potency, allowing the identification of 5.6 nM TGR5 agonist 17.

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