Structural modifications that increase gut restriction of bile acid derivatives

Research output: Contribution to journalArticlepeer-review

Abstract

Bile acid derivatives have been investigated as possible therapeutics for a wide array of conditions, including several for which gut-restricted analogs would likely be preferred. These include the prevention ofClostridioides difficileinfection (CDI) and the treatment of inflammatory bowel disease (IBD). The design of gut-restricted bile acid analogs, however, is complicated by the highly efficient enterohepatic circulation system that typically reabsorbs these compounds from the digestive tract for subsequent return to the liver. Herein, we report that incorporation of a sulfate group at the 7-position of the bile acid scaffold reduces oral bioavailability and increases fecal recovery in two pairs of compounds designed to inhibit the germination ofC. difficilespores. A different approach was necessary for designing gut-restricted bile acid-based TGR5 agonists for the treatment of IBD, as the incorporation of a 7-sulfate group reduces activity at this receptor. Instead, building on our previous discovery that incorporation of a 7-methoxy group into chenodeoxycholic acid derivatives greatly increases their TGR5 receptor potency, we determined that anN-methyl-d-glucamine group could be conjugated to the scaffold to obtain a compound with an excellent mix of potency at the TGR5 receptor, low oral exposure, and good fecal recovery.

Original languageEnglish (US)
Pages (from-to)394-405
Number of pages12
JournalRSC Medicinal Chemistry
Volume12
Issue number3
DOIs
StatePublished - Mar 1 2021

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 Award No. W81XWH-17-1-0635 (PID) & W81XWH-17-1-0636 (AK). Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. TGR5 and VDR agonist assays and LC-MS/ELSD purity determination were performed by Pharmaron, Inc. FXR agonist assays were performed by DiscoverX.

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 Award No. W81XWH-17-1-0635 (PID) & W81XWH-17-1-0636 (AK). Opinions, interpretations, conclusions and recommendations are those of the authors and are not necessarily endorsed by the Department of Defense. TGR5 and VDR agonist assays and LC–MS/ELSD purity determination were performed by Pharmaron, Inc. FXR agonist assays were performed by DiscoverX.

Publisher Copyright:
© The Royal Society of Chemistry 2021.

PubMed: MeSH publication types

  • Journal Article

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