Substituted cyclohexyl compounds as NOP inhibitors
Inventors
Thompson, Jillian Basinger • Bookser, Brett C. • Burley, Scott • Garcia-Reynaga, Pablo • Hudson, Andrew • Peters, Marco • Pratt, Benjamin • Thompson, Aaron • TRAN, Joe • Valdez, Lino
Assignees
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Publication Number
US-12643888-B2
Publication Date
2026-06-02
Expiration Date
Abstract
Substituted cyclohexyl chemical entities of Formula (I):wherein Ra, G, and Rb have any of the values described herein, and compositions comprising such chemical entities; methods of making them; and their use in a wide range of methods, including metabolic and reaction kinetic studies; detection and imaging techniques; radioactive therapies; modulating and treating disorders mediated by nociceptin activity or dopamine signaling; treating neurological disorders, neurodegenerative diseases, depression, and schizophrenia; enhancing the efficiency of cognitive and motor training; and treating peripheral disorders, including renal, respiratory, gastrointestinal, liver, genitourinary, metabolic, and inflammatory disorders.
Core Innovation
The invention relates to substituted cyclohexyl compounds that act as NOP (nociceptin receptor) inhibitors, including specific chemical entities defined as compounds of Formula (I) and sub-formulas (Ia–If) with variable substituents. The disclosure defines the chemical entities in terms of substituted and optionally substituted groups, including aryl, cycloalkyl, heteroaryl, and heterocycloalkyl moieties, and it specifies stereochemical relationships such as cis and trans forms.
A key aspect of the invention is the provision of selected substituted cyclohexyl NOP inhibitor chemical entities, together with pharmaceutically acceptable salts. The disclosed embodiments include compositions and pharmaceutical forms defined using chemical entity and salt definitions, and the document includes definitions for chemical form variants such as solvates, hydrates, conformers, stereoisomers, tautomers, and polymorphs/co-crystals.
The disclosed compounds are presented for use in treating disorders mediated by NOP or nociceptin/orphanin FQ signaling. The description also states broader use cases connected to neuroplasticity and neuroprotection/neurogenesis, and it additionally references detection and imaging techniques, metabolic and reaction kinetic studies, radioactive therapies, and augmentation of cognitive and motor training.
Claims Coverage
The independent claims explicitly present a defined group of specific substituted cyclohexyl carboxamide/amine NOP inhibitor compounds and their pharmaceutically acceptable salts, and a method of treating a disorder involving aberrant or dysregulated NOP-mediated signaling by administering an effective amount of a claim-1 compound or its pharmaceutically acceptable salt. The main inventive coverage is anchored by the specific structural compound selection for NOP inhibition, with dependent coverage including particular members, formulation with a carrier, and treatment by administration for NOP-mediated disorders.
Defined substituted cyclohexyl NOP inhibitor compound group
A compound selected from the group consisting of N-Methyl-4-({2-[(cis)-4-[4-fluoro-2-(trifluoromethyl)phenyl]cyclohexyl]ethyl}amino)oxane-4-carboxamide; N-Methyl-4-({2-[(trans)-4-[4-fluoro-2-(trifluoromethyl)phenyl]cyclohexyl]ethyl}amino)oxane-4-carboxamide; 4-((2-((cis)-4-(4-fluoro-2-methylphenyl)cyclohexyl)ethyl)amino)tetrahydro-2H-pyran-4-carboxamide; 4-({2-[(cis)-4-(2-Chloro-4-fluorophenyl)cyclohexyl]ethyl}amino)oxane-4-carboxamide; 4-({2-[(trans)-4-(2-Chloro-4-fluorophenyl)cyclohexyl]ethyl}amino)oxane-4-carboxamide; N-(2-((cis)-4-(3-methylpyridin-4-yl)cyclohexyl)ethyl) tetrahydro-2H-pyran-4-amine; and pharmaceutically acceptable salts thereof.
Treatment of NOP-mediated disorders by administering an effective amount
A method for treating a disorder with an aberrant or dysregulated NOP-mediated signaling pathway by administering an effective amount of the compound of claim 1, or a pharmaceutically acceptable salt thereof, to a subject in need.
Formulation with pharmaceutically acceptable carrier
A pharmaceutical composition that includes a compound selected from the claim-1 group, together with a pharmaceutically acceptable carrier.
The claim coverage is centered on the explicitly defined group of substituted cyclohexyl NOP inhibitor compounds and pharmaceutically acceptable salts, and it extends to treatment of disorders involving aberrant or dysregulated NOP-mediated signaling by administering an effective amount to a subject in need, with additional dependence for pharmaceutical composition including a pharmaceutically acceptable carrier and selection of particular compound members.
Stated Advantages
Reduced training time, including reduced number of sessions compared to training alone, in post-stroke rehabilitation combined with drug administration.
Documented Applications
Post-stroke rehabilitation paradigms combining drug administration with reduced training time for disorders following stroke, including motor deficit and cognitive deficit.
Treatment of traumatic brain injury (TBI)-associated neurological deficits, including disorders presenting cognitive deficit and long-term memory formation.
Treatment of peripheral disorders linked to altered nociceptin/NOP or reduced dopaminergic signaling.
Combination therapy contexts in which an NOP inhibitor or compound may be used with other CNS agents such as levodopa, antipsychotics, and SSRIs, and with stroke drugs.
Treating disorders mediated by NOP or nociceptin/orphanin FQ signaling, including neurological/CNS and peripheral disorders, as referenced in the provided partial content.
Neuroplasticity and neuroprotection/neurogenesis applications as referenced in the provided partial content.
Detection and imaging techniques as referenced in the provided partial content.
Metabolic and reaction kinetic studies as referenced in the provided partial content.
Radioactive therapies as referenced in the provided partial content.
Cognitive and motor training augmentation as referenced in the provided partial content.
Pharmacological testing context for NOP antagonism using a cell-based cAMP LANCE/TR-FRET assay with pIC50/IC50 results and binding selectivity discussion using NOP versus MOP/KOP/DOP Ki ratios, together with in vivo memory/vas deferens antagonism results in general terms.
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