7-methylation of chenodeoxycholic acid derivatives yields a substantial increase in TGR5 receptor potency

Ali Nakhi, Connor M. Mcdermott, Kristen L. Stoltz, Kristen John, Jon E. Hawkinson, Elizabeth A. Ambrose, Alexander Khoruts, Michael J. Sadowsky, Peter I. Dosa

Research output: Contribution to journalArticlepeer-review

2 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)6824-6830
Number of pages7
JournalJournal of medicinal chemistry
Volume62
Issue number14
DOIs
StatePublished - Jul 25 2019

Bibliographical note

Funding Information:
This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Peer Reviewed Medical Research Program, Investigator Initiated Research Award under Awards W81XWH-17-1-0635 (P.I.D.) and W81XWH-17-1-0636 (A.K.). Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. We thank Michael A. Walters Gunda Georg, and Henry Wong for helpful discussions.

Funding Information:
This work was supported by the Office of the Assistant Secretary of Defense for Health Affairs, through the Peer Reviewed Medical Research Program, Investigator Initiated Research Award under Awards W81XWH-17-1-0635 (P.I.D.) and W81XWH-17-1-0636 (A.K.). Opinions, interpretations, conclusions, and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. We thank Michael A. Walters, Gunda Georg, and Henry Wong for helpful discussions. We thank Lei Wen and Pharmaron, Inc. for performing TGR5 agonist assays.

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