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

PubMed: MeSH publication types

  • Journal Article

Cite this

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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AU - John, Kristen

AU - Hawkinson, Jon E.

AU - Ambrose, Elizabeth A

AU - Khoruts, Alexander

AU - Sadowsky, Michael J

AU - Dosa, Peter I.

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