Inhibitors of the farnesoid x receptor and uses in medicine
Inventors
Gonzalez, Frank J. • Jiang, Changtao • Xie, Cen • Patterson, Andrew D. • Li, Fei • Mitchell, James B. • Amin, Shantu • Desai, Dhimant
Assignees
Penn State Research Foundation • US Department of Health and Human Services
Publication Number
US-10233209-B2
Publication Date
2019-03-19
Expiration Date
2034-08-01
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Disclosed are inhibitors of the farnesoid X receptor, for example of formula (I), wherein R1, R2, R4, X, Y, Z, m, and n are as defined herein, which are useful in treating or preventing obesity, type 2 diabetes/insulin resistance and non-alcoholic fatty liver disease in a mammal in need thereof. Also disclosed is a composition comprising a pharmaceutically suitable carrier and at least one compound of the invention, a method of method of inhibiting a farnesoid X receptor in a mammal, and a method of treating or preventing obesity in a mammal.
Core Innovation
The invention provides inhibitors of the nuclear receptor farnesoid X receptor (FXR), exemplified by compounds of formula (I), which are useful in treating or preventing obesity, type 2 diabetes/insulin resistance, and non-alcoholic fatty liver disease (NAFLD) in mammals in need thereof. These compounds inhibit FXR and affect high fat diet-induced obesity through signal transduction mediated by FXR. Pharmaceutical compositions comprising a pharmaceutically acceptable carrier and at least one compound of the invention are also disclosed, along with methods of administering these compounds to inhibit FXR or to treat or prevent obesity and related metabolic disorders.
The problem being addressed is that obesity has reached epidemic proportions and is linked with chronic diseases including type 2 diabetes, cardiovascular diseases, hepatosteatosis, and cancer. Conventional approaches to treat obesity lack agents that specifically antagonize FXR. Although natural and synthetic FXR agonists are known, no therapeutic agents had been disclosed which antagonize FXR. There is an unmet need for antagonists of the FXR receptor and methods to treat obesity, insulin resistance, and NAFLD by modulating FXR activity.
The invention further reveals that inhibition of intestinal FXR, but not liver FXR, is desirable to treat obesity, insulin resistance, and NAFLD, with preference for compounds having minimal systemic bioavailability to minimize systemic toxicity. The invention also encompasses methods of synthesizing the compound embodiments and demonstrates that certain bile acid derivatives and synthetic compounds, such as glycine-β-muricholic acid (Gly-MCA), act as FXR antagonists mediating beneficial metabolic effects through inhibition of intestinal FXR signaling.
Claims Coverage
The patent includes one independent claim describing compounds selected from specific chemical structures and compositions comprising them, encompassing their synthesis and pharmaceutical use.
Compounds selective for inhibiting farnesoid X receptor
A class of chemical compounds defined by structural formulas (I), (II), and (III) with various substituents and configurations, selected to inhibit FXR activity selectively and including pharmaceutically acceptable salts.
Pharmaceutical compositions with FXR inhibitors
Compositions comprising a pharmaceutically acceptable carrier together with at least one compound or salt according to the invention, formulated for administration to mammals.
Methods for inhibiting FXR and treating metabolic disorders
Methods of inhibiting the farnesoid X receptor in a mammal by administering an effective amount of the compounds or their salts, specifically for treating or preventing obesity, insulin resistance, and non-alcoholic fatty liver disease by targeting intestinal FXR.
Synthetic routes for the compounds
Novel methods for synthesizing compounds of the formulas (I) and (II) involving multi-step chemical reactions starting from defined intermediates, including esterification, protection, reduction, and conjugation steps.
The claims cover novel FXR inhibitory compounds, their pharmaceutical compositions, methods for using these compounds to treat obesity and related metabolic diseases, and methods for their synthesis, focusing on selective inhibition of intestinal FXR to minimize systemic effects.
Stated Advantages
The compounds specifically inhibit intestinal FXR and thereby reduce obesity, insulin resistance, and NAFLD with minimal systemic toxicity.
Inhibiting FXR in the intestine leads to beneficial metabolic effects including decreased body weight gain, improved glucose tolerance, reduced hepatic lipid accumulation, and reduced ceramide levels.
The compounds have utility in treating or preventing diseases associated with FXR signaling, such as obesity and non-alcoholic fatty liver disease, via orally administrable formulations targeting the small intestine.
Documented Applications
Treatment or prevention of obesity in mammals including humans, particularly high-fat diet-induced obesity.
Treatment or prevention of type 2 diabetes and insulin resistance via inhibition of FXR.
Treatment or prevention of non-alcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH).
Use as pharmaceutical compositions administering FXR inhibitors selectively targeting intestinal FXR.
Interested in licensing this patent?