Compositions for the treatment of fibrosis and inflammation
Inventors
Lian, Brian • Masamune, Hiroko • Barker, Geoffrey E.
Assignees
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Publication Number
US-12102646-B2
Publication Date
2024-10-01
Expiration Date
Abstract
The present disclosure is directed to methods of treating fibrotic conditions and inflammation by administration of TRβ agonists. The disclosure provides methods wherein the abnormal deposition of extracellular matrix components, such as collagen, keratin, or elastin, is reduced, either through interaction of TRβ agonists with TGF-β-dependent inflammatory pathways, or by other mechanisms, thereby ameliorating fibrotic symptoms.
Core Innovation
The invention concerns a method of treating fibrosis, a fibrotic condition or a fibrotic symptom in a subject in need thereof, wherein the subject shows abnormal or excessive deposition of collagen. The method comprises administering one or more agonists of Thyroid Receptor Beta (TRβ) to the subject, and the TRβ agonist is defined as one or more compounds having a structure of Formula (A).
The TRβ agonist is defined by Formula (A) with specified substituent constraints for R3′, R4′, and R5′, and includes pharmaceutically acceptable salts thereof. The disclosed compound structures include variable substituents, specific phosphonate-linked features, and example compounds, including Formula I in the description.
The disclosure also frames the fibrosis problem as being linked to inflammatory pathways, including TGF-β-dependent inflammatory pathways, and describes extracellular matrix deposition and collagen accumulation. Fibrosis- and inflammation-related gene markers include Col1a1, Col3a1, ACTA2 (αSMA), LGALS1, ANXA2, and LGALS3.
Claims Coverage
The independent claim set centers on one core inventive concept: treating fibrosis, a fibrotic condition, or a fibrotic symptom in a subject showing abnormal or excessive collagen deposition by administering one or more TRβ agonists having a structure of Formula (A). Dependent refinements specify composition, collagen targets, collagen reduction outcomes, and a liver fibrosis/NASH setting, for a total of six inventive features.
Treating fibrosis by TRβ agonists for abnormal or excessive collagen deposition
A method of treating fibrosis, a fibrotic condition or a fibrotic symptom in a subject in need thereof, where the subject shows abnormal or excessive deposition of collagen, comprising administering one or more agonists of Thyroid Receptor Beta (TRβ) to the subject.
TRβ agonists defined by Formula (A) with specified substituents
The TRβ agonist is one or more compounds having a structure of Formula (A), with specified substituent constraints for R3′, R4′, and R5′, or pharmaceutically acceptable salts thereof.
Formulated composition with pharmaceutically acceptable excipients
The method includes administering a composition containing the compound and one or more pharmaceutically acceptable excipients.
Treatment targeting collagen type 1 deposition
The method is applied to a subject exhibiting abnormal or excessive deposition of collagen type 1.
Administration reduces specific collagen types in tissues
Administering the compound reduces the amount of Type I, Type Ia, or Type III collagen in one or more tissues of the subject.
Liver fibrosis in a non-alcoholic steatohepatitis (NASH) setting
The method is applied to a subject who has liver fibrosis and non-alcoholic steatohepatitis (NASH).
Overall, the claims define a TRβ-agonist administration method for fibrosis associated with abnormal collagen deposition, constrained by Formula (A) compounds and salts, and further refined by compositions with pharmaceutically acceptable excipients, collagen type targets, collagen reduction outcomes, and a liver fibrosis/NASH application.
Stated Advantages
Reduces collagen deposition and extracellular matrix deposition associated with fibrosis.
Reduces fibrosis-related markers including hydroxyproline, Col1a1/Col3a1, ACTA2, LGALS1, ANXA2, and LGALS3.
Amelioration of fibrotic symptoms or conditions associated with abnormal or excessive collagen deposition.
Reductions in extracellular matrix proteins or collagen in tissues, including reductions in Type I, Type Ia, or Type III collagen.
Documented Applications
Treatment of fibrosis, fibrotic conditions, or fibrotic symptoms in a subject showing abnormal or excessive deposition of collagen.
Treatment of liver fibrosis in a subject having non-alcoholic steatohepatitis (NASH).
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