Selective D3 dopamine receptor agonists and methods of their use

Inventors

Sibley, David R. • Moritz, Amy Elizabeth • Free, R. Benjamin • Steiner, Joseph P. • Southall, Noel Terrence • Ferrer, Marc • Hu, Xin • Weiner, Warren S. • Aubé, Jeffrey • Frankowski, Kevin

Assignees

University of North Carolina at Chapel Hill • University of Kansas • US Department of Health and Human Services

Abstract

The disclosure of a compound of Formula (I) or a pharmaceutically acceptable salt thereof (I) The variables W, R1, R2, R3, and R4 are defined in the disclosure. The disclosure provides a compound or salt of Formula (I) together with a pharmaceutically acceptable carrier. The disclosure also provides methods of treating a patient for Parkinson's disease and related syndromes, dyskinesia, especially dyskinesias secondary to treating Parkinson's disease with L-DOPA, neurodegenerative disorders such as Alzheimer's disease and dementia, Huntington's disease, restless legs syndrome, bipolar disorder and depression, schizophrenia, cognitive dysfunction, or substance use disorders, the methods comprising administering a compound of Formula I or salt thereof to the patient. The disclosure provides combination methods of treatment in which the compound of Formula (I) is administered to the patient together with one or more additional active agents.

Core Innovation

The invention provides compounds of Formula I and their pharmaceutically acceptable salts, characterized by variables W, R1, R2, R3, and R4 with specific substituents and configurations as defined. These compounds exhibit selective agonist activity at the D3 dopamine receptor (D3 DAR), with high potency and minimal off-target effects, especially compared to closely related dopamine receptors such as D2 DAR.

The problem solved addresses the lack of highly selective D3 DAR agonists due to the high homology and conserved orthosteric binding sites between the D2 and D3 dopamine receptors. Current drugs and research compounds show relatively poor selectivity, often modulating both receptors, leading to side effects such as impulse control disorders.

Compounds of Formula I demonstrate functional selectivity by promoting β-arrestin translocation and G protein signaling at the D3 DAR with minimal or no activity at the D2 DAR. They bind to the D3 DAR in a unique manner distinct from dopamine and existing agonists, providing superior neuroprotection in neuronal assays compared to pramipexole, a less selective agonist. Pharmaceutical compositions containing these compounds and their use in treating Parkinson's disease, dyskinesia, neurodegenerative disorders, psychiatric disorders, and substance use disorders are also provided.

Claims Coverage

The patent contains multiple independent claims covering compounds of Formula I and their compositions and methods of treatment based on these compounds. Four main inventive features emerge from the independent claims.

The claims focus on novel chemical entities of Formula I selective for the D3 dopamine receptor, their pharmaceutical compositions, and therapeutic methods employing these compounds for a range of central nervous system disorders, highlighting selective activity, structural features, and treatment applications.

Stated Advantages

Documented Applications