Compositions and methods for the inhibition of pruritus
Inventors
Hoon, Mark A. • Solinski, Hans Juergen • Inglese, James • Dranchak, Patricia
Assignees
US Department of Health and Human Services
Publication Number
US-11324725-B2
Publication Date
2022-05-10
Expiration Date
2038-05-14
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Abstract
Pharmaceutical compositions comprising a molecular inhibitor of Npr1 are disclosed. Also disclosed are methods of treating, reducing, or preventing acute and/or chronic pruritus in a mammal comprising administering a pharmaceutical composition comprising a molecular inhibitor of Npr1.
Core Innovation
The invention provides pharmaceutical compositions comprising a pharmaceutically acceptable carrier and a molecular inhibitor of Natriuretic polypeptide receptor 1 (Npr1), a receptor for neuropeptide natriuretic polypeptide B (Nppb). The compositions are intended for treating, reducing, or preventing acute and/or chronic pruritus in mammals. A specific molecular inhibitor exemplified is 1-cyclohexyl-3-(cyclopropylmethyl)-N-((3-methylisoxazol-5-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide, also referred to as compound JS-11.
The problem the invention addresses arises from the limitations of conventional treatments for pruritus, which include topical anti-inflammatory agents, anti-histamines, and emollients. These treatments often fail to effectively manage pruritus in patients due to the inability to eradicate underlying causes, which include various skin and systemic conditions and treatments such as chemotherapy and kidney dialysis. Thus, there is an unmet need for improved compositions and methods for treating pruritus.
The invention also details methods for identifying molecular inhibitors of Npr1 using high-throughput screening technologies, including quantitative high-throughput screening (qHTS). The inhibitors act by various mechanisms including inhibiting Npr1 signaling or the binding of Nppb to Npr1. The inhibitors identified show specific inhibition of Npr1 activity, do not exhibit cytotoxicity, and demonstrate efficacy in reducing itch-related behaviors in animal models, supporting the potential therapeutic application in treating acute and chronic pruritus associated with diverse causes.
Claims Coverage
The patent contains one independent claim defining a pharmaceutical composition with a specific molecular inhibitor of Npr1. The claim coverage centers on the composition and the specific chemical entity used as an inhibitor.
Pharmaceutical composition with a molecular inhibitor of Npr1
The composition comprises a pharmaceutically acceptable carrier and a molecular inhibitor of Natriuretic polypeptide receptor 1 (Npr1), specified chemically as 1-cyclohexyl-3-(cyclopropylmethyl)-N-((3-methylisoxazol-5-yl)methyl)-2-oxo-2,3-dihydro-1H-benzo[d]imidazole-5-carboxamide.
Use of human isoform of Npr1 in composition
The molecular inhibitor specifically targets the human isoform of Npr1 (hNpr1) as the relevant therapeutic target in the composition.
The claims cover a pharmaceutical composition directed at inhibiting Npr1 activity using a defined small molecule inhibitor, focusing on human Npr1 to treat or prevent pruritus in mammals.
Stated Advantages
The molecular inhibitors effectively inhibit Npr1 activity, including hNpr1 and mNpr1, demonstrating therapeutic potential for pruritus.
The inhibitors do not produce cytotoxic effects, nor interfere with luciferase-based assay components, indicating selective and safe action.
The compounds reduce scratching behavior in animal models without impairing motor coordination, indicating efficacy and tolerability.
Identified inhibitors provide a reversible, non-competitive mechanism of action, which may offer advantages over partial agonists like A-71915 that lack efficacy in blocking itch behavior.
Documented Applications
Treatment, reduction, or prevention of acute and/or chronic pruritus in mammals, including humans.
Pruritus associated with skin conditions such as fungal infections, psoriasis, and atopic dermatitis.
Pruritus associated with systemic conditions including renal failure, liver damage, AIDS, polycythemia vera, diabetes, hyperthyroidism, and various cancers.
Pruritus induced by treatments such as chemotherapy agents and kidney dialysis.
Pruritus induced by pruritogens including histamine, chloroquine, endothelin, 2-methyl serotonin, SLIGRL-NH2, and compound 48/80.
Pruritus induced or mediated by cytokines, specifically interleukin-31 (IL-31).
Use of identified molecular inhibitors as medicaments for treating or preventing pruritus.
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