SPAK kinase inhibitors as neuroprotective agents
Inventors
SUN, Dandan • DENG, XIANMING • Zhang, Jinwei • Bhuiyan, Mohammad Iqbal Hossain • Molyneaux, Bradley J.
Assignees
Xiamen University • University of Exeter • University of Pittsburgh • US Department of Veterans Affairs
Publication Number
US-10995061-B2
Publication Date
2021-05-04
Expiration Date
2039-09-30
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Abstract
The present disclosure is concerned with N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)benzamide compounds that are capable of inhibiting SPAK kinase function, methods of treating hypoxic brain injuries due to, for example, ischemic stroke. This abstract is intended as a scanning tool for purposes of searching in the particular art and is not intended to be limiting of the present invention.
Core Innovation
The invention relates to N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)benzamide compounds capable of inhibiting SPAK kinase function. These compounds are useful in treating conditions associated with dysregulation of SPAK kinase function, including hypoxic brain injuries such as those due to traumatic brain injury, ischemic stroke, carbon monoxide poisoning, drowning, choking, suffocating, or cardiac arrest.
The problem being addressed arises from impaired regulation of cellular ion transport critical for brain water homeostasis. Dysregulation in ion transporters and subsequent ionic imbalance leads to brain disorders like ischemic cerebral edema and hydrocephalus, currently treated only by morbid surgical interventions with limited innovation. There remains a need for novel pharmacological modulators of brain salt and water homeostasis to provide non-surgical alternatives, specifically compounds that modulate cation-Cl− cotransporters (CCCs) via inhibition of NKCC1 and/or activation of KCCs through inhibition of SPAK kinase.
Claims Coverage
The patent includes multiple independent claims covering compounds with specific chemical structures and methods of using these compounds to treat hypoxic brain injuries and modify SPAK kinase function. There are four main inventive features extracted from these claims.
Compounds with defined chemical structure to inhibit SPAK kinase
Compounds having a structure represented by Formula 1 with defined R1, R2a, R2b, R2c, R2d, R20, R21a, and R21b groups capable of inhibiting SPAK kinase function for treating disorders related to SPAK dysregulation.
Pharmaceutical compositions containing therapeutically effective amounts of the compounds
Compositions comprising a therapeutically effective amount of at least one compound of the specified structure and a pharmaceutically acceptable carrier, for therapeutic application.
Methods for treating hypoxic brain injury by administering the compounds
Methods of treating hypoxic brain injury in subjects by administering effective amounts of the compounds of defined structures, including those associated with traumatic brain injury, ischemic stroke, and other causes, optionally following diagnosis or subject identification.
Methods for modifying SPAK kinase function in subjects or cells by administering the compounds
Methods for modifying, including inhibiting, SPAK kinase function in a subject or at least one cell by administering effective amounts of the compounds characterized by the specified chemical structures, with optional diagnosis or identification of need for treatment prior to administration.
The claims collectively cover novel chemical compounds structurally defined to inhibit SPAK kinase, pharmaceutical compositions thereof, and methods of using these compounds to treat hypoxic brain injuries and to modify SPAK kinase function in subjects or cells.
Stated Advantages
The compounds potently and selectively inhibit SPAK kinase, thereby reducing cellular ion influx and stimulating chloride extrusion by modulating phosphorylation of NKCC1 and KCC cotransporters.
Intracerebroventricular administration of the compounds normalizes pathological cerebrospinal fluid hypersecretion by decreasing SPAK-mediated phosphorylation of CCCs in choroid plexus.
Systemic administration after ischemic stroke attenuates cerebral infarction and edema and improves neurological outcomes.
The compounds exhibit high kinase selectivity and non-ATP competitive inhibition, minimizing off-target effects.
The compounds show neuroprotective effects in animal models of ischemic stroke and hemorrhagic hydrocephalus.
Documented Applications
Treatment of hypoxic brain injuries including traumatic brain injury, ischemic stroke, carbon monoxide poisoning, drowning, choking, suffocating, or cardiac arrest.
Pharmacological modulation of SPAK kinase function to restore brain water homeostasis and improve neurological function in vivo.
Normalization of cerebrospinal fluid hypersecretion in hemorrhagic hydrocephalus by intracerebroventricular administration.
Attenuation of cerebral infarction and edema and improvement of neurological outcomes after ischemic stroke.
Use in treatment of neurological disorders involving dysregulation of ion transport and brain water homeostasis.
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