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 journalArticle

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

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Chenodeoxycholic Acid
Methylation
Inflammatory Bowel Diseases
Hydroxyl Radical
Type 2 Diabetes Mellitus
Obesity
Acids
Therapeutics

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7-methylation of chenodeoxycholic acid derivatives yields a substantial increase in TGR5 receptor potency. / Nakhi, Ali; Mcdermott, Connor M.; Stoltz, Kristen L.; John, Kristen; Hawkinson, Jon E.; Ambrose, Elizabeth A.; Khoruts, Alexander; Sadowsky, Michael J.; Dosa, Peter I.

In: Journal of Medicinal Chemistry, Vol. 62, No. 14, 25.07.2019, p. 6824-6830.

Research output: Contribution to journalArticle

Nakhi, Ali ; Mcdermott, Connor M. ; Stoltz, Kristen L. ; John, Kristen ; Hawkinson, Jon E. ; Ambrose, Elizabeth A. ; Khoruts, Alexander ; Sadowsky, Michael J. ; Dosa, Peter I. / 7-methylation of chenodeoxycholic acid derivatives yields a substantial increase in TGR5 receptor potency. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62, No. 14. pp. 6824-6830.
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