Methods of treating fibrosis, cancer and vascular injuries

a fibrosis and cancer technology, applied in the field of fibrosis, cancer and vascular injuries, can solve problems such as complicated organ transplantation, and achieve the effects of reducing the number of patients, preventing and treating various disease states, and facilitating the transplantation

Active Publication Date: 2018-11-27
EWHA UNIV IND COLLABORATION FOUND
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0022]Surprisingly, it has now been discovered that a class of 2-pyridyl substituted imidazoles function as potent and selective inhibitors of ALK5 and / or ALK4 and, therefore, have utility in the treatment, prevention, and reduction of various disease states mediated by ALK5 and / or ALK4, such as glomerulonephritis, diabetic nephropathy, lupus nephritis, hypertension-induced nephropathy, renal interstitial fibrosis, renal fibrosis resulting from complications of drug exposure, HIV-associated nephropathy, transplant nephropathy, liver fibrosis due to all etiologies, hepatic dysfunction attributable to infections, alcohol-induced hepatitis, disorders of the biliary tree, cystic fibrosis, pulmonary fibrosis, interstitial lung disease, acute lung injury, adult respiratory distress syndrome, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, pulmonary disease due to infectious or toxic agents, post-infarction cardiac fibrosis, congestive heart failure, dilated cardiomyopathy, myocarditis, intimal thickening, vascular stenosis, hypertension-induced vascular remodeling, pulmonary arterial hypertension, coronary restenosis, peripheral restenosis, carotid restenosis, stent-induced restenosis, atherosclerosis, ocular scarring, corneal scarring, proliferative vitreoretinopathy, glaucoma, intraocular pressure, excessive or hypertrophic scar or keloid formation in the dermis occurring during wound healing resulting from trauma or surgical wounds, peritoneal and sub-dermal adhesion, scleroderma, fibrosclerosis, progressive systemic sclerosis, dermatomyositis, polymyositis, arthritis, osteoporosis, ulcers, impaired neurological function, male erectile dysfunction, Peyronie's disease, Dupuytren's contracture, Alzheimer's disease, Raynaud's syndrome, radiation-induced fibrosis, thrombosis, tumor metastasis growth, multiple myeloma, melanoma, glioma, glioblastomas, leukemia, sarcomas, leiomyomas, mesothelioma, and carcinomas of lung, breast, colon, kidney, ovary, cervix, liver, biliary tract, gastrointestinal tract, pancreas, prostate, head, and neck.

Problems solved by technology

Organ transplantation is complicated in many instances by chronic rejection and for some organs such as the kidney, it is the major forms of graft loss.

Method used

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  • Methods of treating fibrosis, cancer and vascular injuries
  • Methods of treating fibrosis, cancer and vascular injuries
  • Methods of treating fibrosis, cancer and vascular injuries

Examples

Experimental program
Comparison scheme
Effect test

example 2

[0215 suppressed TGF-β1-induced cell migration in MCF10A cells.

[0216]Matrigel Invasion Assay

[0217]The upper surface of Transwells (6.5 mm diameter, 8 μm pore size; Corning, Lowell, Mass., USA) were coated with 20 μL diluted Matrigel (BD Biosciences). 4T1 cells were seeded at 4×104 cells / well on the upper chamber of transwell in serum free medium with or without TGF-β1 (2 ng / mL) in the presence or absence of Example 2. The lower chamber was filled with 10% FBS with TGF-β1 (2 ng / mL) in the presence or absence of Example 2. After incubation for 20 h at 37° C. in 5% CO2, the cells remaining on the upper surface of the membrane were removed with a cotton swab, and DAPI-stained cells remaining on the bottom surface were observed using fluorescence microscopy. Average cell number per view field was obtained from 5 random fields.

[0218]Example 2 suppressed TGF-β1-induced cell invasion in matrigel invasion assay.

[0219]Cell Growth Study

[0220]Either 4T1 cells or MCF10A cells were seeded in 96-w...

example 61

[0228 significantly reduced the number of metastastic lesions in the lung. Significant level of β-casein (a mammary differentiation marker) mRNA was detected in the lung of MMTV / c-Neu mice. Examples 3 and 61 significantly inhibited β-casein mRNA expression level in the lung, demonstrating their anti-metastatic effect.

[0229]Activity of MMP-9 and MMP-2 in the primary mammary tumor was measured by gelatin zymography. Tumor tissues from mice (30 mg) was lysed in 500 μL RIPA buffer (50 mM Tris, 150 mM NaCl, 0.1% sodium dodecyl sulfate, 0.5% sodium deoxycholate, 1% NP-40, protease inhibitor without EDTA) for 10-20 min on ice. Lysates were cleared by centrifugation at 13000 rpm at 4° C. for 10 min. Protein content of supernatants was determined using Micro-BCA protein assay kit (Thermo Scientific). Loading samples were prepared by adding loading buffer (0.5 M Tris, pH 6.8, 50% glycerol, 10% SDS, and 1% bromophenol blue solution) into lysates containing 15 μg of total protein. Loading sampl...

example 3

[0230 significantly inhibited activity of MMP-9 and MMP-2 in the primary mammary tumor.

[0231]Anti-Fibrotic Effect on Bile Duct-Ligated Liver Fibrosis Model

[0232]Six-week-old male Sprague-Dawley (SD) rats were purchased from Orient Bio Inc. In Experiment 1, SD rats weighing 180-200 g were randomly divided into five experimental groups: sham-operated control rats (n=5), sham-operated rats treated with Example 3 (43.6 mg / kg, n=5), bile duct-ligated (BDL) rats (n=10), BDL rats treated with either 21.8 or 43.6 mg / kg of Example 3 (n=10). In Experiment 2, SD rats weighing 180-200 g were randomly divided into five experimental groups: sham-operated control rats (n=5), BDL rats (n=10), BDL rats treated with either 5, 10, or 20 mg / kg of Example 2 (n=10). For BDL, the animals were anesthetized with zoletil (20 mg / kg) and xylazine (10 mg / kg), and the common bile duct was exposed and double-ligated using 3-0 silk. The first ligature was placed below the junction of the hepatic duct, and the seco...

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Abstract

This invention relates to use of inhibitors of the transforming growth factor-β (TGF-β) type I receptor (ALK5) and / or the activin type I receptor (ALK4) in treating, preventing, or reducing fibrosis, cancer, and vascular injuries.

Description

[0001]This application is a continuation-in-part of U.S. patent application Ser. No. 12 / 826,338 filed Jun. 29, 2010 entitled “2-Pyridyl Substituted Imidazoles as Therapeutic ALK5 and / or ALK 4 Inhibitors”, the disclosure of which is incorporated herein by reference.[0002]This application is a reissue of U.S. Pat. No. 8,513,222 B2, which issued from U.S. patent application Ser. No. 13 / 168,342, filed on Jun. 24, 2011.TECHNICAL FIELD OF THE INVENTION[0003]This invention relates to use of inhibitors of the transforming growth factor-β (TGF-β) type I receptor (ALK5) and / or the activin type I receptor (ALK4) in treating, preventing, or reducing fibrosis, cancer, and vascular injuries.BACKGROUND OF THE INVENTION[0004]TGF-β denotes a family of proteins, TGF-β1, TGF-β2 and TGF-β3, which are pleiotropic modulators of cell proliferation and differentiation, wound healing, extracellular matrix production, and immunosuppression. Other members of this superfamily include activins, inhibins, bone m...

Claims

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Application Information

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Patent Type & Authority Patents(United States)
IPC IPC(8): A61K31/437A61K31/5377C07D471/04
CPCA61K31/5377A61P35/00A61K31/444A61P1/16A61P11/00A61K31/437
Inventor KIM, DAE-KEESHEEN, YHUN YHONGJIN, CHENGHUAPARK, CHUL-YONGDOMALAPALLY, SREENUKOTA, SUDHAKAR RAOMADDEBOINA, KRISHNAIAHVURA BALA, SUBRAHMANYAM
Owner EWHA UNIV IND COLLABORATION FOUND
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