Dopamine D3 receptor selective antagonists/partial agonists; method of making; and use thereof
Inventors
Newman, Amy Hauck • Kumar, Vivek • Shaik, Anver Basha
Assignees
US Department of Health and Human Services
Publication Number
US-11299476-B2
Publication Date
2022-04-12
Expiration Date
2037-03-08
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Disclosed herein novel dopamine D3 receptor selective antagonists/partial agonists compounds with high affinity and metabolic stability useful for the treatment of psychiatric and neurological disorders and as research and diagnostic tools. Also disclosed are methods of making the compounds.
Core Innovation
The invention provides novel dopamine D3 receptor selective antagonists and partial agonists of Formula (I) with high affinity for the D3 receptor and excellent metabolic stability. These compounds show improved pharmacologic properties including bioavailability and metabolic stability over prior art 4-phenylpiperazine derivative D3 receptor ligands. The compounds exhibit high selectivity over other dopamine D2-like receptor subtypes such as D2 and D4 receptors and possess drug-like properties suitable for potential therapeutic use.
The compounds of Formula (I) have specific structural features including a heteroaryl group optionally substituted with various substituents, and defined substituents at positions R1 to R5 and linkers which can be single or double bonds or cycloalkyl groups. The invention also discloses pharmaceutical compositions containing these compounds and methods of treatment for neuropsychiatric disorders including substance use disorders, schizophrenia, cognitive disorders, impulsivity, obesity, depression, bipolar disorder, and dyskinesias associated with Parkinson's disease or its treatment with L-DOPA.
The problem addressed relates to the challenge of discovering dopamine D3-selective compounds with drug-like properties due to the high degree of homology with other D2-like receptors, particularly the D2 subtype. Existing compounds lack adequate selectivity, metabolic stability, and appropriate pharmacological profiles for clinical translation. Therefore, there is a recognized need for highly selective, metabolically stable D3 antagonists or partial agonists with suitable drug-like properties for treating neuropsychiatric conditions.
Claims Coverage
The claims disclose 14 main inventive features focusing on specific compounds of Formula (I), pharmaceutical compositions comprising these compounds, and methods of treatment using them.
Specific highly selective D3 receptor antagonist compounds
Claims disclose a list of specific compounds including various stereoisomers and radioisotopes characterized by structural features such as piperazinyl, hydroxybutyl or fluorobutyl linkers, and heteroaryl carboxamide groups like indole-2-carboxamide and benzofuran-2-carboxamide derivatives.
Use of radioisotope-labeled compounds
The compounds may comprise radioisotopes such as tritium, deuterium, 11C, 13C, 14C, 18F, or combinations thereof for research or diagnostic purposes.
Pharmaceutical compositions containing the compounds
Pharmaceutical compositions comprising the claimed compounds with at least one pharmaceutically acceptable carrier are claimed. These may be formulated as injectable fluids, aerosols, creams, gels, tablets, capsules, syrups, ophthalmic solutions, or transdermal patches.
Package comprising pharmaceutical compositions with instructions
A package including the pharmaceutical composition in a container together with instructions for treating disorders such as substance use disorder, schizophrenia, depression, bipolar disorder, or Parkinson's disease-related dyskinesia.
Methods of treating neuropsychiatric disorders with the compounds
Methods for treating substance use disorder, schizophrenia, depression, bipolar disorder, or Parkinson's disease/dyskinesia by administering a therapeutically effective amount of the claimed compounds to patients in need.
Methods including pharmaceutically acceptable carriers
Methods for treating mentioned disorders by providing compounds of Formula (I) along with at least one pharmaceutically acceptable carrier.
Treatment methods targeting opioid or cannabinoid substance use disorders
The substance use disorders treated by the compounds include opioid or cannabinoid addictions.
Specific subsets of compounds with stereoisomers and pharmaceutically acceptable salts
Claims specify various subsets of individual compounds and their stereoisomers and pharmaceutically acceptable salts for use in the compositions and methods.
The claims cover specific novel selective dopamine D3 receptor antagonists/partial agonists and their stereoisomers and radioisotopes, pharmaceutical compositions containing these compounds, packaging with instructions, and therapeutic methods for neuropsychiatric disorders, particularly substance use disorders including opioids and cannabinoids, schizophrenia, depression, bipolar disorder, and Parkinson's disease dyskinesias.
Stated Advantages
Compounds exhibit high potency and selectivity for dopamine D3 receptors with metabolic stability superior to prior art compounds.
Improved bioavailability and pharmacological properties enable potential clinical application with reduced side effects due to lower effective doses.
Effectiveness demonstrated in animal behavioral models of drug abuse and withdrawal including oxycodone and cannabis.
Compound 29 shows of high metabolic stability in liver microsomes across species including humans.
Compounds lack binding to opioid or cannabinoid receptors, suggesting specificity and reduced off-target effects.
Compound 29 blocks reinforcing effects of oxycodone without affecting analgesia, indicating potential as addiction treatment while preserving pain relief.
Documented Applications
Treatment of substance use disorders including opioid and cannabinoid (marijuana) abuse.
Treatment of schizophrenia and related mental disorders.
Treatment of cognitive disorders.
Treatment of impulsivity, obesity, depression, and bipolar disorders.
Treatment of dyskinesias associated with Parkinson's disease or treatment of Parkinson's disease with L-DOPA.
Use as research tools in dopamine receptor subtype studies, biomarkers, or in medical diagnostics such as PET ligand development using radioisotopes.
Interested in licensing this patent?