Methods to decrease triglyceride synthesis in the liver
Inventors
Matsuda, Kazuko • Ogura, Masatsune
Assignees
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Publication Number
US-12239620-B2
Publication Date
2025-03-04
Expiration Date
Abstract
Described herein are methods for decreasing triglyceride synthesis and/or decreasing triglyceride accumulation in the liver of a subject, wherein the methods comprise administering to the subject a compound of Formula (I): a metabolite thereof, or a pharmaceutically acceptable salt thereof.
Core Innovation
Methods are disclosed for decreasing triglyceride synthesis or triglyceride accumulation in a liver of a subject by administering an effective amount of a phenoxyalkylcarboxylic acid compound of Formula (I), including a metabolite of Formula (I) of Formula (IB), or a pharmaceutically acceptable salt thereof. The compounds are defined by substituent parameters where m is 2–5 and n is 3–8, and X1 and X2 are each independently a sulfur atom, oxygen atom, sulfinyl group, or a sulfonyl group, provided that X1 and X2 cannot both be oxygen atoms.
Specific embodiments are provided for Formula (IA) and Formula (IB), including MN-001 and MN-002. The subject is diagnosed with insulin resistance, pre-diabetes, or diabetes, and the compounds are positioned to act in the liver context in these subjects.
In vitro biological data are presented using HepG2 cells, where MN-001 inhibits triglyceride accumulation induced by arachidonic acid and/or the LXR agonist T0901317, and is associated with corresponding effects on CD36 mRNA expression and ABCG1 mRNA expression. A Phase 2 randomized, double-blind, placebo-controlled study design is described for MN-001 in NAFLD with type 2 diabetes and hypertriglyceridemia, with co-primary endpoints including change in liver fat measured by MRI-PDFF and fasting serum triglycerides at week 24.
Claims Coverage
The partial content provides two independent claims. Across both, the inventive features center on administering an effective amount of a phenoxyalkylcarboxylic acid of Formula (I), or a metabolite or pharmaceutically acceptable salt, to subjects diagnosed with insulin resistance, pre-diabetes, or diabetes, for decreasing liver triglyceride synthesis or triglyceride accumulation.
Decreasing hepatic triglyceride synthesis in insulin resistance, pre-diabetes, or diabetes
A method to decrease triglyceride synthesis in a liver of a subject by administering to the subject an effective amount of a compound of Formula (I), a metabolite thereof, or a pharmaceutically acceptable salt thereof, wherein m is 2, 3, 4, or 5, n is 3, 4, 5, 6, 7, or 8, X1 and X2 each independently represent a sulfur atom, oxygen atom, sulfinyl group, or a sulfonyl group, provided that X1 and X2 cannot both be oxygen atoms, and wherein the subject is diagnosed with insulin resistance, pre-diabetes, or diabetes.
Decreasing hepatic triglyceride accumulation in insulin resistance, pre-diabetes, or diabetes
A method to decrease triglyceride accumulation in a liver of a subject by administering to the subject an effective amount of a compound of Formula (I), a metabolite thereof, or a pharmaceutically acceptable salt thereof, wherein m is 2, 3, 4, or 5, n is 3, 4, 5, 6, 7, or 8, X1 and X2 each independently represent a sulfur atom, oxygen atom, sulfinyl group, or a sulfonyl group, provided that X1 and X2 cannot both be oxygen atoms, and wherein the subject is diagnosed with insulin resistance, pre-diabetes, or diabetes.
Both independent claims cover administering a Formula (I) compound, or a metabolite or pharmaceutically acceptable salt, defined by m, n, and the X1/X2 heteroatom constraints to subjects diagnosed with insulin resistance, pre-diabetes, or diabetes, with the claimed liver-directed outcome being either decreased triglyceride synthesis or decreased triglyceride accumulation.
Stated Advantages
Decreases triglyceride synthesis in a liver of a subject.
Decreases triglyceride accumulation in a liver of a subject.
Documented Applications
Patients with NAFLD with type 2 diabetes and hypertriglyceridemia in a Phase 2 randomized, double-blind, placebo-controlled study design for MN-001, using co-primary endpoints of change in liver fat (MRI-PDFF) and fasting serum triglycerides at week 24.
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