SPAK kinase inhibitors as neuroprotective agents
Inventors
SUN, Dandan • DENG, XIANMING • Zhang, Jinwei • Bhuiyan, Mohammad Iqbal Hossain • Molyneaux, Bradley J.
Assignees
Xiaman University • Xiamen University • University of Exeter • University of Pittsburgh • US Department of Veterans Affairs
Publication Number
US-11414379-B2
Publication Date
2022-08-16
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 or disorders associated with dysregulation of SPAK kinase function, particularly hypoxic brain injuries such as traumatic brain injury, ischemic stroke, carbon monoxide poisoning, drowning, choking, suffocating, or cardiac arrest. The compounds also modify SPAK kinase function by inhibiting its activity, thus affecting ion transport mediated by cation-chloride cotransporters (CCCs) that regulate cell volume and brain water homeostasis.
The problem being solved arises from the critical role of coordinated ion and water transport in maintaining brain homeostasis. Impaired ionic homeostasis in the choroid plexus epithelium (CPe) can cause hydrocephalus, and defective cell volume regulation leads to cerebral edema, especially after ischemic stroke. Current treatments for ischemic cerebral edema and hydrocephalus rely on surgical interventions such as decompressive hemicraniectomy or CSF shunting, which are associated with morbidity and have not improved significantly. There is a compelling need for pharmacological agents that modulate brain salt and water homeostasis by targeting SPAK kinase regulation of CCCs as non-surgical therapeutic options.
Claims Coverage
The claims cover methods of treating hypoxic brain injuries via administration of specified N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)benzamide compounds, focusing on their effective amounts and particular structures, and subject types.
Method for treating hypoxic brain injury by administering specific compounds
Administering to a subject an effective amount of at least one compound selected from a group of N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)benzamide derivatives defined by substituents R1, R2a-d, R20, R21a,b, with specified conditions on substitution patterns and pharmaceutically acceptable salts.
Treatment using compounds with defined substitution patterns
Use of compounds with substituents R1 selected from —OH, —SR20, and —NR21aR21b (with restrictions), and R2a-d independently selected from hydrogen, halogen, nitro, cyano, hydroxy, thiol, amino, various alkyl and substituted alkyl groups, for treatment of hypoxic brain injury.
Method involving treating hypoxic brain injury due to ischemic stroke or related causes
Administering effective amounts of compounds to subjects diagnosed or in need of treatment for hypoxic brain injuries caused by ischemic stroke, traumatic brain injury, or related conditions such as carbon monoxide poisoning, drowning, choking, suffocation, or cardiac arrest.
The patent claims center on the therapeutic use of specific N-(5-chloro-4-((4-chlorophenyl)(cyano)methyl)-2-methylphenyl)benzamide compounds for treating hypoxic brain injuries by modulating SPAK kinase function, with precise structural definitions and subject applicability outlined.
Stated Advantages
The compounds potently and selectively inhibit SPAK kinase, effectively modulating phosphorylation of NKCC1 and KCC cotransporters to restore ion and water homeostasis.
Intracerebroventricular administration normalizes pathological CSF hypersecretion in hemorrhagic hydrocephalus by decreasing SPAK-mediated phosphorylation.
Systemic administration post-ischemic stroke attenuates cerebral infarction and edema, improving neurological outcomes in vivo.
The compounds overcome issues associated with direct NKCC or KCC targeting by modulating upstream SPAK kinase non-competitively for ATP.
They show high kinase selectivity and favorable inhibition profiles compared to prior inhibitors such as Closantel and WNK463.
They provide neuroprotection and preserve white and gray matter after ischemic stroke, as demonstrated by MRI and DTI studies.
Documented Applications
Treatment of hypoxic brain injuries including traumatic brain injury, ischemic stroke, carbon monoxide poisoning, drowning, choking, suffocating, or cardiac arrest.
Normalization of cerebrospinal fluid hypersecretion in hemorrhagic hydrocephalus by intracerebroventricular delivery of SPAK kinase inhibitors.
Reduction of ischemic cerebral edema, infarct volume, and neurological deficits following ischemic stroke via systemic administration.
Use in both male and female hypertensive and normotensive animal models to provide neuroprotection and improve neurological function post-stroke.
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