Aminonaphthoquinone compounds for treatment and/or prevention of fibrosis diseases
Inventors
Yen, Yun • Liou, Jing-Ping • LIN, Chien Huang
Assignees
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Publication Number
US-11833122-B2
Publication Date
2023-12-05
Expiration Date
Abstract
The invention relates to the use of a compound of Formula (I) as described herein and its effective dose in the prevention and/or treatment of fibrosis diseases. The compound can effectively prevent and/or treat a fibrosis disease without cytotoxicity or genotoxicity.
Core Innovation
The invention provides aminonaphthoquinone compounds of Formula I, including pharmaceutically acceptable salt, solvate, or prodrug forms, for preventing and/or treating fibrosis diseases. The disclosed therapeutic approach involves administering an effective amount of a compound of Formula I to a subject for anti-fibrotic activity.
The document specifies fibrosis indications including skin, lung, renal, liver, intestinal, cystic fibrosis, cardiac, and uterine leiomyoma and adenomyosis, including idiopathic pulmonary fibrosis. The invention is framed as an anti-fibrosis treatment delivered by administering an effective amount of an aminonaphthoquinone compound according to Formula I.
The document also discloses biological assay use of MPT0L056 (L056). In WI-38 fibroblasts, L056 inhibits CTGF/collagen I and shows no effect on cell viability in an MTT assay, and in vivo it is effective in bleomycin lung fibrosis and CCl4 liver fibrosis mouse models with dose-dependent improvement.
Claims Coverage
The claim coverage centers on treating liver fibrosis by administering a specific benzamide compound or its salt, solvate, or prodrug. The independent and dependent claim features add effective mg/kg/day dosage ranges and optional co-administration with a second anti-fibrosis agent, including selected therapeutic agents and antibodies.
Treatment of liver fibrosis with a specific Formula I benzamide aminonaphthoquinone
Administering an effective amount of 4-(((3-chloro-1,4-dioxo-1,4-dihydronaphthalen-2-yl)amino)methyl)-N-(pyridin-4-yl)benzamide, or a pharmaceutically acceptable salt, solvate or prodrug thereof, as an active ingredient to the subject for treatment of liver fibrosis.
Effective dose ranges for the formula I compound
Administering the active ingredient in an effective amount within specified mg/kg/day dosage ranges.
Co-administration with a second anti-fibrosis agent
Co-administering the active ingredient with a second anti-fibrosis agent simultaneously, separately, or sequentially.
Second anti-fibrosis agent selection including anti-fibrotic drugs and antibodies
Selecting the second anti-fibrosis agent from pirfenidone, nintedanib, LOXL2 antibody (simtuzumab), IL-13 antibody (lebrikizumab), αVβ6 antibody (STX-100), CTGF antibody (FG-3019), tipelukast, aerosol pirfenidone, and MN-001.
Overall, the claim coverage centers on treating liver fibrosis by administering a specific Formula I aminonaphthoquinone benzamide or related forms, with dependent coverage directed to specified effective-dose ranges and combination therapy with selected anti-fibrosis agents, including small molecules and antibodies.
Stated Advantages
Prevents and/or treats fibrosis diseases by administering aminonaphthoquinone compounds of Formula I.
Inhibits fibrotic markers induced by TGF-β/ET-1/thrombin, including CTGF, collagen, α-SMA, and fibronectin.
Shows in vivo efficacy in bleomycin lung fibrosis and CCl4 liver fibrosis models with improved histologic fibrosis scores.
Inhibits CTGF/collagen I in WI-38 fibroblasts.
Shows no effect on cell viability in an MTT assay.
Effective in bleomycin lung fibrosis with dose-dependent improvement.
Effective in CCl4 liver fibrosis with dose-dependent improvement.
Documented Applications
Treatment of liver fibrosis in a subject using a compound of Formula I or related forms as an active ingredient.
Fibrosis diseases including skin, lung, renal, liver, intestinal, cystic fibrosis, cardiac, and uterine leiomyoma and adenomyosis, including idiopathic pulmonary fibrosis.
Biological assay use of MPT0L056 (L056) in WI-38 fibroblasts for CTGF/collagen I inhibition and assessment in an MTT cell viability assay.
Use of L056 in bleomycin lung fibrosis mouse model with dose-dependent improvement.
Use of L056 in CCl4 liver fibrosis mouse model with dose-dependent improvement.
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