Inhibitors of mPTP
Inventors
Miller, Neil • Ouvry, Gilles • Rutter, Richard • Ladduwahetty, Tammy • THOMSON, CHRISTOPHER • KULAGOWSKI, Jan • Rowley, Michael • TUFFNELL, Andrew • Negoita-Giras, Gabriel • Stewart, Mark • ARMSTRONG, Rachel • Boyd, Susan
Assignees
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Publication Number
US-12491185-B2
Publication Date
2025-12-09
Expiration Date
Abstract
The invention relates to compounds of formula (I), and related aspects.
Core Innovation
The invention relates to compounds of defined triazole- or pyrimidine-carboxamide chemical structures, including N-(substituted) triazole-carboxamides and N-(substituted) pyrimidine-carboxamides selected from a listed group. The compounds are characterized by specific fluorinated aryl substituents, cyclopropyl-containing side chains, and defined stereochemical assignments including (R) and (S) configurations for relevant chiral centers. The selected compounds may be present as a salt and/or solvate.
The document further describes substituted amine and amide intermediates and final triazole-3-carboxamide compounds built around a 1-methyl-5-oxo-4,5-dihydro-1H-1,2,4-triazole-3-carboxamide motif and a 5-fluoro-4-oxo-3H-pyrimidine-2-carboxamide motif. The disclosed examples include defined benzyl, cycloalkyl, cyclobutyl, cyclopropyl, fluoro, difluoro, chloro, and other substituted side-chain patterns, with characterization data such as NMR, LC-MS, and UPLC reported for quality control. [procedural detail omitted for safety]
The document also associates the defined compounds with use in treating disease or disorder by inhibiting mitochondrial permeability transition pore (mPTP). In this context, the claimed embodiments include administering an effective amount of a compound or a pharmaceutically acceptable salt and/or solvate to a human subject for mPTP-related therapeutic effect, and a pharmaceutical composition comprising the compound and at least one pharmaceutically acceptable carrier.
Claims Coverage
The consolidated claim coverage centers on a defined set of triazole-carboxamide and pyrimidine-carboxamide compounds, including salts and/or solvates, with stereochemical refinement for specific (R) or (S) embodiments. In addition, the claim set covers pharmaceutical compositions and a human treatment method by inhibiting mitochondrial permeability transition pore (mPTP).
Defined triazole- and pyrimidine-carboxamide compound set
A compound or a salt and/or solvate thereof selected from listed N-(substituted) triazole-carboxamides and N-(substituted) pyrimidine-carboxamides, including the specifically named fluorinated triazole-carboxamide and fluorinated pyrimidine-carboxamide structures.
Stereochemically specified embodiments
The compound of the defined class in which stereochemistry is specified as (R) or (S) for relevant listed compounds, including (R)-configured triazole-carboxamide and pyrimidine-carboxamide embodiments.
Pharmaceutical composition comprising the defined compound
A pharmaceutical composition comprising a compound or a salt and/or solvate thereof according to claim 1 and at least one pharmaceutically acceptable carrier.
Method of treating a human disease or disorder by mPTP inhibition
A method of treating a disease or disorder in a human subject by inhibiting mitochondrial permeability transition pore (mPTP), comprising administering an effective amount of a compound or pharmaceutically acceptable salt and/or solvate according to claim 1.
Specified disease and disorder treatment scope
The method is directed to treating a disease or disorder selected from a listed group including Parkinson's disease, dementia with Lewy bodies, Alzheimer's disease, amyotrophic lateral sclerosis, multiple sclerosis, frontal temporal dementia, chemotherapy induced neuropathy, Huntington's disease, spinocerebellar ataxias, progressive supranuclear palsy, hereditary spastic paraplegia, Duchenne muscular dystrophy, congenital muscular dystrophy, traumatic brain injury, Friedreich's ataxia, AIDS dementia complex, depressive disorders, schizophrenia, epilepsy, myocardial infarction, stroke, kidney ischemia reperfusion injury, organ damage during transplantation, hepatic steatosis, diabetes, diabetic neuropathy, diabetic retinopathy, cognitive decline, obesity and feeding behaviours, non-alcoholic fatty liver disease, acute pancreatitis, systemic lupus, organ failure in sepsis, hepatitis, bone repair, bone weakness in aging in osteoporosis, sarcopenia, chronic kidney disease associated with APOL1 genetic variants, chronic kidney disease, Reye syndrome, Leber's hereditary optic neuropathy and disorders, Facial onset sensory and motor neuronopathy, Primary lateral sclerosis, Progressive muscular atrophy, Inclusion body myopathy associated with early-onset Paget disease of the bone, Frontotemporal lobar degeneration dementia, Perry disease, Chronic traumatic encephalopathy, Severe traumatic brain injury, Hippocampal sclerosis dementia, Limbic-predominant age-related TDP-43 encephalopathy, and Cerebral age-related TDP-43 with sclerosis.
Overall, the claim coverage focuses on specific triazole- or pyrimidine-carboxamide compounds, their salts and/or solvates, stereochemically specified embodiments, pharmaceutical compositions, and human treatment methods in which therapeutic effect is linked to inhibition of mitochondrial permeability transition pore (mPTP).
Stated Advantages
Treating a disease or disorder in a human subject by inhibiting mitochondrial permeability transition pore (mPTP).
Many stereoisomeric compounds are mPTP inhibitors with high potency, based on reported mPTP pIC50 results.
Documented Applications
Inhibition of mitochondrial permeability transition pore (mPTP) activity in biological assays, including isolated rat liver and rat brain mitochondria assays and a human platelet mitochondria assay.
Treating a disease or disorder in a human subject by inhibiting mitochondrial permeability transition pore (mPTP).
Pharmaceutical treatment and/or prophylactic treatment of diseases and disorders by inhibiting mitochondrial permeability transition pore (mPTP), including neurodegenerative/degenerative diseases, ischemia and re-perfusion injury, metabolic diseases, inflammatory/autoimmune diseases, and diseases of aging.
Therapeutic/prophylactic use of compounds of formula (I) and salts/solvates for mitochondrial diseases, including preventing/treating Reye syndrome and Leber's hereditary optic neuropathy.
Therapeutic/prophylactic use for disorders associated with TDP-43 proteinopathy, including ALS and frontotemporal dementia/FTLD as enumerated in the partial content.
Therapeutic/prophylactic use for diseases associated with fibrosis, including chronic kidney disease, idiopathic pulmonary fibrosis, NASH, PBC, and systemic sclerosis.
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