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 language | English (US) |
|---|---|
| Pages (from-to) | 6824-6830 |
| Number of pages | 7 |
| Journal | Journal of medicinal chemistry |
| Volume | 62 |
| Issue number | 14 |
| DOIs | |
| State | Published - 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.
Publisher Copyright:
© 2019 American Chemical Society.
