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Novel compounds and methods of treating or ameliorating an il-1r-mediated disease or disorder using same

Inactive Publication Date: 2017-07-20
DREXEL UNIV
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The invention provides compounds that can be used to treat diseases or disorders that are caused by the action of a protein called IL-1R. The compounds can be administered to patients to help alleviate the symptoms of these diseases or disorders. The compounds have a specific formula and can be selected from a group of compounds described in the patent. The technical effect of the invention is to provide new compounds that can be used to treat IL-1R-mediated diseases or disorders.

Problems solved by technology

On the other hand, diffuse scleroderma progresses rapidly and is quite disabling, affecting a large area of the skin and internal organs, such as the kidneys, esophagus, heart and / or lungs.
The prognosis is dire for limited cutaneous scleroderma patients who escape pulmonary complications (they generally die of lung failure within 30 years post diagnosis), but is even worse for those with the diffuse cutaneous disease, particularly in patients who are older and / or male.
Currently there is a critical lack of approved therapies for IL-1R-mediated diseases or disorders, such as the orphan disease scleroderma.

Method used

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  • Novel compounds and methods of treating or ameliorating an il-1r-mediated disease or disorder using same
  • Novel compounds and methods of treating or ameliorating an il-1r-mediated disease or disorder using same
  • Novel compounds and methods of treating or ameliorating an il-1r-mediated disease or disorder using same

Examples

Experimental program
Comparison scheme
Effect test

example 1

Studies

[0297]A hybrid structure based screening method was used to design small molecule inhibitors of IL-1R that bind at the antagonist site. Using the 21 amino acid peptide complexed IL-1R crystal structure as a template, a four point hybrid pharmacophore was designed and screened against a library of 3 million small molecules. The resulting 662 hits were filtered for drug-like properties, and 230 hits that cleared the filtering schemes were docked to the well-prepared IL-1R protein antagonist binding site using the molecular docking program—GOLD (version 4.1).

[0298]The docked protein-ligand complexes were ranked using customized scoring schemes and five high ranking compounds (KA199, KA494, KA529, KA680, and KA862) were selected for in vitro validation. Molecular docking studies revealed that the compounds bind to the same site as the antagonist peptide or endogenous protein and hence can block the interaction of IL-1 with the IL-1R (FIG. 1).

example 2

Synthesis

[0299]SSc fibroblasts were cultured with selected molecules of the invention, and total collagen synthesis was assessed with hydroxyproline. Four compounds demonstrated efficacy at 10 mM (FIG. 5). KA862 and KA494 were selected for further in vitro evaluation.

example 3

of IL-1 Signaling

[0300]FIG. 6 illustrates the finding that compounds of the invention directly blocks IL-1 signaling in normal fibroblasts.

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Abstract

The present invention provides compounds useful for treating or preventing an IL-1R-mediated disease or disorder. In certain embodiments, the disease or disorder comprises scleroderma.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]The present application claims priority under 35 U.S.C. §119(e) to U.S. Provisional Patent Application No. 62 / 032,668, filed Aug. 4, 2014, which application is incorporated herein by reference in its entirety.BACKGROUND OF THE INVENTION[0002]Scleroderma, also known as systemic sclerosis, is a chronic systemic autoimmune disease that primarily affects the skin and is characterized by hardening (sclerosis) of the skin and internal organs due to the excessive accumulation of collagen. Further, scleroderma is characterized by damage to small blood vessels, activation of T lymphocytes and production of antinuclear antibodies.[0003]Limited scleroderma involves cutaneous manifestations that mainly affect the hands, arms and face, with the following common manifestations: calcinosis (deposition of calcium nodules in the skin), Raynaud's phenomenon (exaggerated vasoconstriction in the hands, with fingers undergoing white-blue-red color transitions...

Claims

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Application Information

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IPC IPC(8): C07D417/14A61K31/427C07C237/52C07D263/56C07D401/04A61K31/4439A61K31/36A61K45/06A61K31/167
CPCC07D417/14A61K45/06A61K31/427C07C237/52C07D263/56C07D401/04A61K31/4439A61K31/36A61K31/167A61K38/00C07D309/32C07D215/54C07D317/58C07D317/66C07D249/08C07D471/04C07D487/04C07D491/052C07D493/04C07D513/04C07D211/90C07C317/44A61K31/4162A61K31/47A61K31/519C07C2601/08C07C2601/14A61P1/04A61P11/00A61P17/00A61P19/02A61P25/08A61P29/00A61P31/00A61P35/00A61P35/02A61P37/02A61P37/06A61P9/00A61P3/10A61K2300/00
Inventor KORTAGERE, SANDHYAARTLETT, CAROL M.
Owner DREXEL UNIV
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