Pyrazolylacylpyrazoline compounds and method for treating pain
Inventors
Meroueh, Samy • WHITE, Fletcher A. • OBUKHOV, Alexander G.
Assignees
US Department of Veterans Affairs • Indiana University Bloomington
Publication Number
US-11999720-B2
Publication Date
2024-06-04
Expiration Date
2039-09-19
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Abstract
This invention relates to pyrazolylacylpyrazoline compounds or pharmaceutically acceptable salts thereof, and for the use of the compounds to treat neurological disorders.
Core Innovation
This invention relates to pyrazolylacylpyrazoline compounds or pharmaceutically acceptable salts thereof, and the use of these compounds to treat neurological disorders, particularly pain. The compounds are defined by Formula (1) or Formula (1a) with various specified substituents. They are used to modulate protein-protein interactions between pore and auxiliary subunits of voltage-gated ion channels in nerve cells, such as CaVα1 and CaVβ subunits, and can be incorporated into pharmaceutical compositions with carriers, diluents, or excipients.
The background identifies that voltage-gated calcium channels in the central nervous system are critical in synaptic transmission and signal transduction. The interaction between pore-forming α1 subunits and auxiliary β subunits is a key protein-protein interaction. Current calcium channel blockers used for pain management exhibit numerous off-target effects and narrow therapeutic windows, presenting a clinical problem. Therefore, there is a need for non-addictive compounds treating pain that avoid drawbacks of existing medicines.
The summary describes compounds of Formula (1) or (1a) with specified R1 to R4 substituents and pharmaceutically acceptable salts. Methods are provided for treatment of neurological disorders by administering effective amounts of these compounds, as well as methods to modulate the interaction between pore and auxiliary subunits of voltage-gated ion channels in nerve cells. Compounds have been synthesized, characterized, and shown to inhibit the CaVα1-CaVβ3 interaction, affect CaV2.2 channel current properties, and reduce mechanical hypersensitivity in animal models of neuropathic pain.
Claims Coverage
The patent claims cover multiple inventive features centered on novel pyrazolylacylpyrazoline compounds, their pharmaceutical compositions, methods of treating neurological disorders, including pain, and modulation of protein-protein interactions of voltage-gated ion channels. Independent claims mainly encompass the chemical compounds themselves and methods of use.
Novel pyrazolylacylpyrazoline compounds
Compounds of Formula (1) or Formula (1a) are disclosed with specific substituents R1 to R4, including (C1-C4 alkyl)-CO2H, tetrazole substituted phenyl, phenyl, methoxy substituted phenyl, pyridinyl, alkoxy substituted phenyl, and phenyl substituted pyridyl. Certain compounds exclude specific structures and include pharmaceutically acceptable salts.
Pharmaceutical compositions
Compositions comprising compounds of Formula (1) or Formula (1a) or pharmaceutically acceptable salts thereof along with pharmaceutically acceptable carriers, diluents, or excipients suitable for administration by various routes.
Methods of treating neurological disorders
Methods to treat neurological disorders such as pain by administering an effective amount of compounds of Formula (1) or Formula (1a) or their pharmaceutically acceptable salts to mammals in need.
Modulation of protein-protein interactions
Methods to modulate protein-protein interaction between the pore and auxiliary subunits (such as CaVα1 and CaVβ3) of a voltage-gated ion channel in nerve cells by contacting the nerve cells with effective amounts of the compounds of Formula (1) or Formula (1a) or their pharmaceutically acceptable salts.
The independent claims cover novel pyrazolylacylpyrazoline compounds with defined substituents, pharmaceutical compositions containing these compounds, methods of treating neurological disorders and pain by administering these compounds, and methods for modulating specific protein-protein interactions of voltage-gated ion channels in nerve cells.
Stated Advantages
The compounds are effective over a wide dosage range, allowing flexibility in therapeutic administration.
They provide a non-addictive alternative for pain management with potentially fewer off-target effects compared to clinically approved calcium channel blockers.
Compounds showed modulation of voltage-gated calcium channel activity by decreasing current density and shifting voltage dependence of activation, which underlies their therapeutic effect.
Certain compounds demonstrated efficacy in reversing mechanical hypersensitivity in animal models of neuropathic pain, lasting longer than some comparator compounds.
Documented Applications
Use in treating neurological disorders including pain, chronic pain, diabetic neuropathy, neuropathy secondary to nerve trauma, trigeminal neuralgia, postherpetic neuralgia, cancer pain, and AIDS-related neuropathy.
Modulation of protein-protein interaction between pore and auxiliary subunits of voltage-gated calcium channels, specifically CaVα1 and CaVβ or CaVβ3 subunits, in nerve cells.
Pharmaceutical use in compositions for oral, parenteral, topical, nasal, inhaled, or rectal administration for treatment of such neurological disorders.
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