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-12162861-B2
Publication Date
2024-12-10
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 discloses novel dopamine D3 receptor selective antagonists and partial agonists compounds of Formula (I), their stereoisomers, radioisotopes, and pharmaceutically acceptable salts. These compounds exhibit high affinity and metabolic stability, which was unexpectedly not achieved by prior dopamine D3 receptor selective antagonists/partial agonists. The compounds have high selectivity over the closely related D2 and D4 receptor family members and represent an advancement over previously known 4-phenylpiperazine derivative D3 receptor ligands by offering improved pharmacological properties, bioavailability, and metabolic stability in vivo.
The compounds of Formula (I) include various heteroaryl groups optionally substituted, and different substituents on the phenylpiperazine and linking portions, with provisos on substitution patterns ensuring selectivity and binding affinity. The compounds are formulated into pharmaceutical compositions with pharmaceutically acceptable carriers. Methods of treating neuropsychiatric disorders including substance use disorders, schizophrenia and related mental disorders, cognitive disorders, impulsivity, obesity, depression, bipolar disorder, and dyskinesias associated with Parkinson's disease or its treatment are provided by administering these compounds.
The problem addressed arises from the high amino acid homology among the dopamine D2-like receptor subtypes, especially D2 and D3, which presents a significant challenge in developing dopamine D3-selective compounds with appropriate drug-like properties, including metabolic stability for potential clinical applications. There is a recognized need for highly selective dopamine D3 antagonists or partial agonists that are metabolically stable and suitably drug-like for translation into treatments of neuropsychiatric conditions and substance use disorders.
Claims Coverage
The patent contains multiple claims including independent claims directed to the compound of Formula (I), pharmaceutical compositions comprising said compounds, packages containing such compositions, and methods of treatment using the compounds. The inventive features focus on the novel chemical structures, selective receptor targeting, administration forms, and therapeutic uses.
Compound of Formula (I) with specific heteroaryl and substitution patterns
The invention claims compounds of Formula (I) featuring a heteroaryl group Ar selected from benzofuranyl, benzothienyl, imidazolyl, imidazo[1,2-a]pyridinyl, imidazo[2,1-b]thiazolyl, or indolyl, optionally substituted with 1 to 3 substituents independently selected from specified alkyl, haloalkyl, alkoxy, haloalkoxy, hydroxyl, carboxyl, amino, nitro, alkanoyl, alkylamino, or halogen groups. The claims specify preferred substitution patterns and linkers such as a single bond, double bond, cyclohexyl, or cyclopropyl ring as part of the structure.
Pharmaceutical compositions comprising the compounds
The claims cover pharmaceutical compositions including a compound of Formula (I) or a pharmaceutically acceptable salt thereof combined with at least one pharmaceutically acceptable carrier. These compositions may be formulated into various dosage forms such as injectable fluids, aerosols, creams, gels, tablets, capsules, syrups, ophthalmic solutions, or transdermal patches.
Methods of treating neuropsychiatric and substance use disorders
Methods encompass providing therapeutically effective amounts of compounds of Formula (I) to patients to treat substance use disorders, schizophrenia, depression, bipolar disorders, or dyskinesias associated with Parkinson's disease or its treatment with L-DOPA. The substance use disorder includes opioids and cannabinoids. Methods also include administration along with pharmaceutically acceptable carriers.
Use of radioisotopes for imaging and diagnostic purposes
The claims include compounds incorporating radioisotopes such as tritium, deuterium, 11C, 13C, 14C, 18F, or combinations thereof, enabling applications as research tools or medical diagnostic agents, including PET ligand development.
The claims collectively cover novel dopamine D3 receptor selective compounds with defined structural features, effective pharmaceutical formulations, methods of use in treating neurological and psychiatric disorders, and use in diagnostic imaging, thereby securing protection for the chemical entities, their therapeutic applications, and diagnostic utilities.
Stated Advantages
The compounds of Formula (I) have unexpectedly high affinity and excellent metabolic stability not previously achieved by dopamine D3 receptor selective antagonists/partial agonists.
They show high selectivity over homologous dopamine receptor family members such as D2 and D4 receptors.
The compounds have improved pharmacological properties, bioavailability, and metabolic stability in vivo compared to prior similar ligands.
High potency and D3 receptor selectivity of the compounds may allow for lower dose administration, potentially limiting side effects.
Compound (±)-29 demonstrates effectiveness in behavioral models of drug abuse and withdrawal, indicating therapeutic suitability with less interference in analgesic effects.
Documented Applications
Treatment of psychiatric and neurological disorders including substance use disorders (such as cocaine, heroin, methamphetamine, various opioids, cannabis, alcohol, nicotine), schizophrenia and related mental disorders, cognitive disorders, impulsivity, obesity, depression, bipolar disorder, and dyskinesias associated with Parkinson's disease or L-DOPA treatment thereof.
Use as research and diagnostic tools for studying dopamine receptor subtypes.
Use as PET ligand or MRI diagnostic agent when incorporating radioisotopes.
Attenuation of oxycodone self-administration, oxycodone seeking behavior, and naloxone-precipitated conditioned place aversion in rat models of opioid abuse.
Reduction of THC self-administration and THC-induced reinstatement in squirrel monkeys, indicating potential use in marijuana abuse treatment.
Attenuation of oxycodone-induced conditioned place preference and locomotor sensitization in rodents, indicating efficacy in drug reinforcement and addiction models.
Interested in licensing this patent?