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
  • 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.