Large-conductance potassium channel modulators, compositions thereof, methods of manufacturing thereof, and methods of use thereof
Inventors
Raffa, Robert B. • Pergolizzi, Joseph V.
Assignees
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Publication Number
US-12721850-B2
Publication Date
2026-09-01
Expiration Date
Abstract
Disclosed herein are methods of treating a disease or condition modulated by large-conductance potassium channels, the methods including administering, to a patient in need thereof, an effective amount of a large-conductance potassium channel modulating compound. Exemplary disease or conditions that may be treated include, without limitations, protection against ischemia and hypoxia at multiple points throughout the body, as well as respiration stimulation in the presence of such conditions (both local and systemic). Also described herein are pharmaceutical compositions for use in the methods of treatment of a disease or condition modulated by large-conductance potassium channels, and methods of preparing such pharmaceutical compositions.
Core Innovation
The invention relates to large-conductance potassium channel modulators having a scaffold defined by Formula (I), including pharmaceutically acceptable salt forms, in which substituent- and linkage-variable definitions specify different structural embodiments. The description defines how these variables are selected and combined to produce a range of Formula (I) BK channel modulator compounds, including compounds defined by sub-formulas (II-a/II-b/III-a/III-b/IV/V) and enumerated compound examples.
Pharmaceutical compositions are provided that comprise a therapeutically effective amount of one or more BK channel modulator compounds according to Formula (I). The compositions include specific exemplified compound(s) and multiple structural sub-sets, together with pharmaceutically acceptable excipients and carriers.
The compositions are described in different dosage forms and regimen formats, including single-dose or multi-dose presentations, and may be lyophilized or pre-mixed. The compositions may include additional active agents and are formulated for broad administration routes using pharmaceutically acceptable components such as excipients, carriers, and formulation additives, with specified dosage forms and containers.
Claims Coverage
The provided independent claims cover three treatment categories—neurological, cardiac, and cerebral disorders—using Formula (I) large-conductance potassium channel modulating compounds. Across the dependent claims, the coverage specifies agonist or antagonist functional characterization, the channel structural regions modulated, channel localization at pre-synaptic and/or post-synaptic sites, and administration routes selected from a defined list.
Treating neurological disorders with Formula (I) large-conductance potassium channel modulators
Administering, to a patient in need thereof, an effective amount of a large-conductance potassium channel modulating compound selected from compound(s) of Formula (I), wherein the disease or condition is a neurological disorder selected from epilepsy, paroxysmal dyskinesia, or schizophrenia.
Modulating pore gate and/or voltage sensing domain for neurological treatment
The compound modulates either or both of the pore gate or the voltage sensing domain of a large-conductance potassium channel.
Modulating RCK1 and/or RCK2 for neurological treatment
The compound modulates either or both RCK1 and RCK2 of the large-conductance potassium channel.
Channel location at pre-synaptic and/or post-synaptic sites for neurological treatment
The large-conductance potassium channel is located at either the pre-synaptic site, the post-synaptic site, or both.
Selected administration routes for neurological treatment
The administration route is chosen from a listed set of administration routes.
Treating cardiac ischemia or cardiac hypoxia with Formula (I) large-conductance potassium channel modulators
Administering, to a patient in need thereof, an effective amount of a large-conductance potassium channel modulating compound selected from compound(s) of Formula (I), wherein the disease or condition is a cardiac disorder selected from cardiac ischemia or cardiac hypoxia.
Antagonist activity for cardiac treatment
The compound used is an antagonist.
Modulating pore gate and/or voltage sensing domain for cardiac treatment
The compound modulates either the pore gate and/or the voltage sensing domain of a large-conductance potassium channel.
Modulating RCK1 and/or RCK2 for cardiac treatment
The compound modulates RCK1 and/or RCK2 of a large-conductance potassium channel.
Channel location at pre-synaptic and/or post-synaptic sites for cardiac treatment
The large-conductance potassium channel is located at one or both of a presynaptic or postsynaptic site.
Selected administration routes for cardiac treatment
The administration route is selected from the listed routes.
Treating cerebral ischemia or cerebral hypoxia with Formula (I) large-conductance potassium channel modulators
Administering, to a patient in need thereof, an effective amount of a large-conductance potassium channel modulating compound selected from compound(s) of Formula (I), wherein the disease or condition is a cerebral disorder selected from cerebral ischemia or cerebral hypoxia.
Agonist activity for cerebral treatment
The compound is an agonist.
Antagonist activity for cerebral treatment
The compound is an antagonist.
Modulating pore gate and/or voltage sensing domain for cerebral treatment
The compound modulates one or both of the pore gate or the voltage sensing domain of the large-conductance potassium channel.
Modulating RCK1 or RCK2 for cerebral treatment
The compound modulates one or both of the RCK1 or the RCK2 of the large-conductance potassium channel.
Selected administration routes for cerebral treatment
The administration route is selected from oral, intravenous, nasal, inhalational, topical, buccal, rectal, pleural, peritoneal, vaginal, intramuscular, subcutaneous, transdermal, epidural, intratrachael, otic, intraocular, or intrathecal.
Across the independent claims, the core claim coverage centers on administering effective amounts of Formula (I) large-conductance potassium channel modulating compounds to treat neurological, cardiac, and cerebral disorders. The dependent claim refinements further specify whether the compound acts as an agonist or antagonist, define modulation targets at the pore gate/voltage sensing domain and/or RCK1/RCK2 subdomains, optionally constrain channel localization to pre-synaptic and/or post-synaptic sites, and limit administration routes to enumerated options.
Stated Advantages
Not explicitly described in patent.
Documented Applications
Treating neurological disorders selected from epilepsy, paroxysmal dyskinesia, or schizophrenia using Formula (I) large-conductance potassium channel modulating compounds.
Treating cardiac disorders selected from cardiac ischemia or cardiac hypoxia using Formula (I) large-conductance potassium channel modulating compounds.
Treating cerebral disorders selected from cerebral ischemia or cerebral hypoxia using Formula (I) large-conductance potassium channel modulating compounds.
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