Small molecule modulators of gut bacterial bile acid metabolism

Small molecule inhibitors of BSH enzymes modulate bile acid metabolism, addressing the need to treat metabolic and gastrointestinal diseases by inhibiting the conversion of primary to secondary bile acids, thus affecting metabolic and immune processes effectively.

CA3137308CActive Publication Date: 2026-06-30PRESIDENT & FELLOWS OF HARVARD COLLEGE
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Patent Information

Authority / Receiving Office
CA · CA
Patent Type
Patents
Current Assignee / Owner
PRESIDENT & FELLOWS OF HARVARD COLLEGE
Filing Date
2020-05-08
Publication Date
2026-06-30

AI Technical Summary

Technical Problem

There is an unmet need for a potent and selective agent to inhibit bile salt hydrolase (BSH) enzymes expressed by human gut bacteria to treat diseases such as cancer, inflammation, obesity, diabetes, and gastrointestinal diseases, and to understand bile acid physiology in the host subject.

Method used

Development of small molecule compounds, including those of Formulae (I)-(XVIII), which act as inhibitors of BSH, modulating bile acid metabolism by inhibiting the conversion of primary to secondary bile acids, thereby affecting metabolic and immune processes.

Benefits of technology

The compounds effectively inhibit BSH activity in gut bacteria, reducing deconjugated bile acids, modulating bile acid profiles, and treating conditions like diabetes, obesity, and various gastrointestinal and inflammatory diseases without significant off-target effects or toxicity.

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Abstract

Described herein are methods and compositions related to inhibiting bile salt hydrolase (BSH) and uses thereof. Provided herein is a method for treating a metabolic disorder (e.g., diabetes, obesity), gastrointestinal disease (e.g., a gastrointestinal infection; inflammatory bowel disease (IBD); appendicitis; Crohn's disease (CD); ulcerative colitis (UC); gastritis; enteritis; esophagitis; pancreatitis; diabetes; hepatitis; liver diseases (e.g., Non-alcoholic Fatty Liver Disease (NAFLD); non-alcoholic steatohepatitis (NASH); hepatitis A; hepatitis B; hepatitis C; autoimmune hepatitis; and cirrhosis of the liver) gastroesophageal reflux disease (GERD); celiac disease; diverticulitis; food intolerance; ulcer; infectious colitis; irritable bowel syndrome; leaky gut; and cancer), cancer (e.g., cancer of the digestive system, liver cancer), or an inflammatory disease (e.g., Crohn's disease, inflammatory bowel disease, ulcerative colitis, pancreatitis, hepatitis, appendicitis, gastritis, diverticulitis, celiac disease, food intolerance, enteritis, ulcer, gastroesophageal reflux disease (GERD), psoriatic arthritis, psoriasis, and rheumatoid arthritis) in a subject in need thereof comprising administering to a subject a compound of Formulae (I) -(XVIII).
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