Methods for treatment of fibrotic diseases
Inventors
Han, Ruolan • Northrup, Jon • Kasibhatla, Srinivas • Horrigan, Stephen • Larson, Jeffrey
Assignees
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Publication Number
US-11298346-B2
Publication Date
2022-04-12
Expiration Date
Abstract
Methods for treatment of fibrotic diseases using compounds of formula Iwherein RA is hydrogen,R7 and R8 are independently selected from H and SO2NR3R4,one of R7 and R8 is hydrogen, andR1, R2, R3, and R4 are each independently selected from H, alkyl, heteroalkyl, cycloalkyl, arylcycloalkyl, aryl, heteroaryl, heterocycloalkyl, and each of NR1R2 and NR3R4 can independently combine to form a heterocycloalkyl, and wherein said alkyl, heteroalkyl, cycloalkyl, arylcycloalkyl, aryl, heteroaryl, or heterocycloalkyl may be optionally substituted,or a pharmaceutically acceptable salt, ester, amide, stereoisomer, geometric isomer or prodrug thereof.
Core Innovation
The invention relates to methods for treating pulmonary fibrosis by administering to a patient a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof. The therapeutic method prevents beta-catenin from association with trans-ducin-beta-like 1 (TBL1) protein in the patient, thereby modulating the WNT/beta-catenin pathway activity described in the specification.
The invention further identifies a specific compound exemplified as Tegavivint (BC-2059) and includes pharmaceutically acceptable salt, ester, amide, stereoisomer, geometric isomer, and prodrug forms associated with the Formula I compound. The specification emphasizes that Tegavivint prevents beta-catenin association with TBL1, which leads to beta-catenin degradation as part of the described mechanism.
The specification provides multiple administration routes for delivering the therapeutically effective amount of the Formula I compound, including systemic/intravenous, intratracheal/aerosolized inhalation, intranasal, and topical delivery. The document also describes formulation approaches that support aerosol delivery, including a formulation containing poloxamer 188 and sorbitol and a nano-milled suspension.
Claims Coverage
The independent claim defines a method of treating pulmonary fibrosis with a therapeutically effective dose range, together with the functional requirement that the compound prevents beta-catenin from associating with TBL1. Dependent claims further refine the administration routes and include specific formulation components.
Treating pulmonary fibrosis by preventing beta-catenin/TBL1 association
A method of treating pulmonary fibrosis in a patient in need thereof by administering a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof, wherein the method prevents beta-catenin from association with trans-ducin-beta-like 1 (TBL1) protein in the patient.
Therapeutically effective dose range
The therapeutically effective dose is from about 0.0001 to about 1000 mg/kg/day.
Aerosolized delivery for pulmonary fibrosis treatment
The method administers the treatment by aerosolized delivery.
Intratracheal delivery for pulmonary fibrosis treatment
The method is performed by administering the claimed treatment through intratracheal delivery.
One or more specified administration routes
The method is administered using one or more specified delivery routes including intravenous, parenteral, oral, buccal, inhalation, intranasal, rectal, intra-lesional, intraperitoneal, intradermal, transdermal, subcutaneous, intra-arterial, intracardiac, intraventricular, intracranial, intratracheal, intrathecal administration, intramuscular injection, intravitreous injection, and topical application.
Poloxamer and sorbitol solution formulation
The compound is formulated in a solution containing poloxamer and sorbitol.
Nano-milled suspension formulation
The compound is formulated as a nano-milled suspension.
Overall, the claims cover treating pulmonary fibrosis with a Formula I compound or pharmaceutically acceptable salt at a specified dose range, where the key inventive function is preventing beta-catenin association with TBL1, with dependent claim refinements directed to aerosolized or intratracheal delivery and specific formulation forms.
Stated Advantages
Prevents beta-catenin from association with TBL1, leading to beta-catenin degradation.
Improves lung compliance in bleomycin-induced pulmonary fibrosis models.
Reduces soluble collagen/hydroxyproline in bleomycin-induced pulmonary fibrosis models.
Documented Applications
Treating pulmonary fibrosis in a patient in need thereof.
Treating Dupuytren’s contracture and scleroderma-related disorders.
Treating liver cirrhosis.
Treating keloids.
Treating chronic kidney disease.
Treating chronic graft rejection.
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