Small molecule CMKLR1 antagonists in inflammatory disease
Inventors
Malhotra, Sanjay • Kumar, Vineet • LaJevic, Melissa • Pandrala, Mallesh • Zabel, Brian A.
Assignees
US Department of Veterans Affairs • Leland Stanford Junior University
Publication Number
US-11730705-B2
Publication Date
2023-08-22
Expiration Date
2040-04-13
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Abstract
α-NETA analogs are provided for the treatment of inflammatory disease.
Core Innovation
The invention relates to compositions and methods for interfering with biological processes associated with chemokine-like receptor-1 (CMKLR1) signaling, including the regulation of inflammatory diseases such as psoriasis and demyelinating inflammatory diseases like multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE). In particular, the invention provides α-NETA analogs and formulations thereof as CMKLR1 antagonists useful for the treatment or prevention of these diseases.
The problem addressed is the unmet need for improved therapies for inflammatory autoimmune diseases such as MS. Existing FDA-approved disease-modifying therapies, including dimethyl fumarate and FTY720, have only partial efficacy and can exhibit undesirable side effects such as lymphopenia and increased susceptibility to infections. Moreover, agents targeting broad leukocyte trafficking pathways may lead to systemic immune defects. Therefore, agents that selectively target key inflammatory cell subsets via CMKLR1 inhibition offer potential superior therapeutic strategies.
Claims Coverage
The patent contains two independent claims directed to methods of decreasing psoriasis in a subject by administration of certain compounds.
Methods of decreasing psoriasis using specific compounds
Administering to a subject an effective amount of a compound selected from specified α-NETA analogs for decreasing psoriasis.
Specified effective dose ranges for topical treatment
An effective dose range for the compounds of about 0.01 mg/m2 to 500 mg/m2 surface area for treatment of psoriasis.
Reduction of acanthosis by treatment
Using compounds that reduce acanthosis, a characteristic skin thickening in psoriasis, as part of the treatment method.
The claims cover methods of treating psoriasis by administering specific α-NETA analog compounds, including defined dose ranges and effects such as reduction of acanthosis.
Stated Advantages
α-NETA is safe and superior to Tecfidera (dimethyl fumarate) in suppressing clinical signs of experimental autoimmune encephalomyelitis (EAE) in vivo.
α-NETA has a reasonable in vitro safety profile with limited off-target cytochrome P450 enzyme inhibition and low cardiotoxicity risk due to minimal hERG channel inhibition.
α-NETA and its methoxy-substituted analogs have improved target potency and enhanced efficacy in vivo in suppressing demyelinating disease and psoriasis models.
Selective targeting of CMKLR1 by small molecule antagonists can lead to improved treatment of autoimmune and inflammatory disorders compared to broader immune modulators.
Documented Applications
Treatment or prevention of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) by antagonizing CMKLR1 using α-NETA analogs.
Treatment of psoriasis, including experimental psoriasis models such as imiquimod-induced psoriasis in mice, by administration of α-NETA and improved analog compounds.
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