Methods of treating cardiac edema, neuromyelitis optica, and hyponatremia
Inventors
Pelletier, Marc F. • Farr, George William • Mcguirk, Paul Robert • Hall, Christopher H. • Boron, Walter F.
Assignees
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Publication Number
US-11084778-B2
Publication Date
2021-08-10
Expiration Date
Abstract
The present invention relates to the use of selective aquaporin inhibitors, e.g., of aquaporin-4 or aquaporin-2, e.g., certain phenylbenzamide compounds, for the prophylaxis, treatment and control of aquaporin-mediated conditions, e.g., diseases of water imbalance, for example edema (particularly edema of the brain and spinal cord, e.g., following trauma or ischemic stroke, as well as the edema associated with glioma, meningitis, acute mountain sickness, epileptic seizures, infections, metabolic disorders, hypoxia, water intoxication, hepatic failure, hepatic encephalopathy, diabetic ketoacidosis, abscess, eclampsia, Creutzfeldt-Jakob disease, and lupus cerebritis, as well as edema consequent to microgravity and/or radiation exposure, as well as edema consequent to invasive central nervous system procedures, e.g., neurosurgery, endovascular clot removal, spinal tap, aneurysm repair, or deep brain stimulation, as well as retinal edema), as well as hyponatremia and excess fluid retention, and diseases such as epilepsy, retinal ischemia and other diseases of the eye associated with abnormalities in intraocular pressure and/or tissue hydration, myocardial ischemia, myocardial ischemia/reperfusion injury, myocardial infarction, myocardial hypoxia, congestive heart failure, sepsis, and neuromyelitis optica, as well as migraines, as well as to novel assays for identifying aquaporin inhibitors.
Core Innovation
The document describes a method of treating or controlling a disease or condition mediated by an aquaporin selected from cardiac edema, neuromyelitis optica, and hyponatremia. The method comprises administering to a human patient in need thereof an effective amount of an aquaporin inhibitor of formula 1a, in free or pharmaceutically acceptable salt form.
The disclosed therapeutic use is further characterized by specifying particular edema-related or electrolyte-related etiologies within the overall aquaporin-mediated framework. Cardiac edema is associated with cardiac ischemia or interruption of blood flow to the heart, while hyponatremia is caused by heart failure, liver cirrhosis, nephrotic disorder, or syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Additional embodiments restrict the inhibitor structure and its substituent identities within formula 1a. These refinements include specifying particular allowable substituents for the R groups and specifying R6 as a phosphono group with substitution or no substitution, or identifying the aquaporin inhibitor as the compound of formula 1a shown in chemical structure representations.
Claims Coverage
The relevant independent claim is a single method claim directed to treating or controlling aquaporin-mediated diseases or conditions in a human patient using an aquaporin inhibitor of formula 1a with defined structural substituent selections. The claim includes multiple dependent refinements that focus on specific indications or etiologies and on constrained structural embodiments, including free or pharmaceutically acceptable salt form and particular R-group selections.
Treating aquaporin-mediated disease or condition in a human patient with a formula 1a aquaporin inhibitor
A method of treating or controlling a disease or condition mediated by an aquaporin selected from cardiac edema, neuromyelitis optica, and hyponatremia by administering to a human patient in need thereof an effective amount of an aquaporin inhibitor of formula 1a, in free or pharmaceutically acceptable salt form.
Using the formula 1a inhibitor with a defined hyponatremia etiology
A method wherein the hyponatremia is caused by heart failure, liver cirrhosis, nephrotic disorder, or syndrome of inappropriate antidiuretic hormone secretion (SIADH).
Treating cardiac edema associated with cardiac ischemia or interruption of blood flow
A method wherein cardiac edema is caused by cardiac ischemia or other interruption of blood flow to the heart.
Constraining R-group selections within formula 1a
A method wherein R1, R3, and R5 are selected from trifluoromethyl, chloro, fluoro, or bromo, and R2 and R4 are H.
Specifying R6 as a phosphono group
A method characterized by specifying that R6 is a phosphono group that may be substituted or unsubstituted.
Employing the formula 1a compound shown in chemical structure representations
A method wherein the aquaporin inhibitor is the compound of formula 1a shown in the provided chemical structure images.
Overall, the claim coverage is centered on administering an effective amount of a formula 1a aquaporin inhibitor to a human patient to treat or control aquaporin-mediated cardiac edema, neuromyelitis optica, or hyponatremia, with dependent claim refinements specifying particular etiologies and constraining structural embodiments of formula 1a, including defined R-group selections, salt/free form, and a phosphono R6 embodiment.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating or controlling aquaporin-mediated disease or condition selected from cardiac edema, neuromyelitis optica, and hyponatremia by administering an aquaporin inhibitor of formula 1a to a human patient in need thereof.
Identifying aquaporin inhibitors using a high-throughput cell-volume assay under hypertonic and hypotonic conditions in aquaporin-expressing cells [procedural detail omitted for safety].
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