Sphingosine 1 phosphate receptor agonists for neuroprotection
Inventors
Meadows, Kristen R. Taylor • Skolnick, Brett • Dalvie, Deepak
Assignees
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Publication Number
US-11207301-B2
Publication Date
2021-12-28
Expiration Date
Abstract
Methods of treating conditions for which S1P-mediated neuroprotection is medically indicated, comprising administering to a subject in need thereof an agonist of the sphingosine 1-phosphate receptor (S1P receptor); such as a compound having the following structure (See Formula 1): or a pharmaceutically acceptable salt, stereoisomer, homolog, hydrate or solvate thereof.
Core Innovation
The invention relates to neuroprotection through administering S1P receptor agonists, with a focus on S1P1 agonists and compounds having specified structures, including pharmaceutically acceptable salts, stereoisomeric forms, homologs, hydrates, and solvates. The disclosed embodiments include structures (II) and (III) and multiple depicted small-molecule variants, with representative compound lists and tables. The compounds are framed as neuroprotective agents for diseases involving neurodegeneration and neuroinflammation.
The invention addresses treating a patient with a disease selected from Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and Rett syndrome. The described therapeutic effect is linked to reductions in spinal cord inflammation and demyelination, immune-related measures including T cell expansion, monocyte infiltration, and microglia expansion, and reduced brain volume loss. The disclosure also includes decreased MAO-B activity and increased AKT phosphorylation and ERK phosphorylation in cortical astrocytes.
The disclosed chemical structures show shared scaffold core features with variable substituents, including R^a, R1, Rc, Rb1/Rb2, cyano groups, heterocycle ring elements, aryl groups, heteroaryl substituents, and alkyl or heterocycle terminal groups. The embodiments refer to representative structures such as II-1 to II-7, III-1 to III-4, and I-10 through I-35, indicating multiple compound variants under the same structural family.
Claims Coverage
The independent claim coverage centers on treating a patient with Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, or Rett syndrome by administering a therapeutically effective amount of a compound having one of the specified structures, including pharmaceutically acceptable salts, stereoisomers, homologs, hydrates, or solvates. Across the provided claim summaries, the inventive features repeatedly identify the disease selection and the structurally defined S1P receptor agonist compound family, with additional dependent features tied to efficacy evidence.
Treating selected neurodegenerative diseases with a structurally defined compound
Treating a patient with a disease selected from Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, or Rett syndrome by administering a therapeutically effective amount of a compound having one of the following structures, or a pharmaceutically acceptable salt, stereoisomer, homolog, hydrate, or solvate thereof.
Compound structures (II) and (III) for S1P receptor agonists
The compound is a S1P receptor agonist provided as chemical structures (II) and (III) with variable substituents including R1, Rc, Rb1/Rb2, and related chemical forms.
Efficacy evidence in spinal cord and immune-related outcomes
Dependent claim coverage specifies reduced spinal cord inflammation, reduced T cell expansion, decreased monocyte infiltration into the spinal cord, reduced microglia expansion into the spinal cord, or any combination of these outcomes.
Reduced brain volume loss and MAO-B activity
Dependent claim coverage specifies reduced brain volume loss and reduced MAO-B activity.
Overall, the claim coverage is anchored by administering therapeutically effective amounts of structurally defined S1P receptor agonist compounds, or acceptable pharmaceutical variants, to patients with Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, or Rett syndrome. The dependent features refine the coverage with efficacy evidence involving spinal cord inflammation, immune-cell measures, brain volume loss, and MAO-B activity.
Stated Advantages
Neuroprotection is supported through reductions in spinal cord inflammation and demyelination.
Reduced immune-cell activity is supported by reductions in T cell expansion, decreased monocyte infiltration, and reduced microglia expansion into the spinal cord.
Reduced brain volume loss is supported as a neurodegeneration-related outcome.
Decreased MAO-B activity is supported.
Increased AKT phosphorylation and ERK phosphorylation in cortical astrocytes are stated.
Providing treatment of Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and Rett syndrome.
Reducing spinal cord inflammation.
Reducing T cell expansion, decreasing monocyte infiltration into the spinal cord, limiting microglia expansion into the spinal cord, or combinations thereof.
Reducing brain volume loss.
Documented Applications
Neuronal preservation and improved gait/kinematics are documented in a cuprizone/ozanimod-related context.
A relapsing multiple sclerosis context is referenced with brain volume loss outcomes.
Applications are described across Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and Rett syndrome treatment contexts.
Treating a patient having a disease selected from Parkinson's disease, amyotrophic lateral sclerosis, Alzheimer's disease, and Rett syndrome by administering a therapeutically effective amount of a compound having the specified structures, including salts, stereoisomers, homologs, hydrates, and solvates.
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