Pyridazinone compounds and uses thereof
Inventors
Hunt, Kevin • Koch, Kevin • Russell, Alan • Schlachter, Stephen • Winship, Paul • Steele, Chris
Assignees
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Publication Number
US-12012395-B2
Publication Date
2024-06-18
Expiration Date
Abstract
Substituted pyridazinone compounds, conjugates, and pharmaceutical compositions for use in the treatment of neuromuscular diseases, such as Duchenne Muscular Dystrophy (DMD), are disclosed herein. The disclosed compounds are useful, among other things, in the treating of DMD and modulating inflammatory inhibitors IL-1, IL-6 or TNF-α.
Core Innovation
The disclosed method treats activity-induced muscle damage, a neuromuscular condition, a metabolic myopathy, or a movement disorder by administering a substituted pyridazinone compound or salt of Formula (III′) to a subject in need thereof. The compounds function as selective fast skeletal muscle myosin II inhibitors, reducing skeletal-muscle contraction with selectivity for type II muscle over slow type I skeletal, cardiac, and lung muscle fibers. Structural options for Formula (III′) include defined substituent and ring-closure selections.
The described approach addresses contraction-related muscle injury and conditions involving skeletal muscle activity, including muscle spasticity, muscular dystrophies, and McArdle's syndrome. In documented muscle-injury measures, selected substituted pyridazin-3(2H)-one compounds demonstrate lower post-injury force loss and lower tibialis anterior mass increase compared to vehicle. Documented therapeutic regimens also describe combination therapies with corticosteroids, exon-skipping agents, and dystrophin or microdystrophin gene therapy.
Claims Coverage
The provided claims identify one independent claim directed to a therapeutic method comprising two main inventive features.
Treatment of specified conditions
The method treats activity-induced muscle damage, a neuromuscular condition selected from Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy 1 or 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, limb girdle muscular dystrophy, tendinitis, or carpal tunnel syndrome, McArdle’s syndrome, or a movement disorder comprising muscle spasticity associated with multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, cerebral palsy, injury, or listed traumatic events.
Administration of a Formula (III′) compound or salt
The method comprises administering to a subject in need thereof a compound or salt of Formula (III′), wherein the claim elements define structural options including selections for Y, A, R1–R10, R30, R31, n, p, and heteroaryl R2, with optional ring formations involving R1 and R3, R4, or R5.
The independent claim combines administration of a defined compound or salt of Formula (III′) with the treatment of activity-induced muscle damage, neuromuscular conditions, McArdle’s syndrome, or movement disorders comprising muscle spasticity.
Stated Advantages
Selective fast skeletal muscle myosin II inhibition reduces skeletal muscle contraction by about 5–90% and contraction-related muscle injury while seeking to preserve physical activity.
The compounds limit unwanted inhibition of respiratory and cardiac function by selectively targeting type II muscle while minimally affecting slow type I skeletal muscle, cardiac muscle, and lung muscle fibers.
A dependent claim specifies an amount of the compound or salt sufficient to reduce involuntary muscle contractions by at least 10%.
Selected compounds demonstrate lower post-injury force loss and lower tibialis anterior mass increase compared to vehicle in reported muscle-injury measures.
Documented Applications
Treatment of activity-induced muscle damage.
Treatment of neuromuscular conditions comprising Duchenne muscular dystrophy, Becker muscular dystrophy, myotonic dystrophy 1 or 2, facioscapulohumeral muscular dystrophy, oculopharyngeal muscular dystrophy, limb girdle muscular dystrophy, tendinitis, and carpal tunnel syndrome.
Treatment of McArdle’s syndrome.
Treatment of movement disorders comprising muscle spasticity associated with multiple sclerosis, Parkinson’s disease, Alzheimer’s disease, cerebral palsy, injury, or traumatic events including stroke, traumatic brain injury, spinal cord injury, hypoxia, meningitis, encephalitis, phenylketonuria, and amyotrophic lateral sclerosis.
Combination treatment with corticosteroids (including deflazacort or prednisone), exon-skipping agents (including eteplirsen or ataluren), and dystrophin or microdystrophin gene therapy.
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