Triazaspiro D2/D3 Antagonists for PONV and Gastroparesis
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Solution Overview
Problem
Current antiemetic drugs and gastric motility agents are insufficient in effectively addressing post-operative nausea and vomiting (PONV) and gastroparesis, despite extensive research, indicating a need for more efficacious and safe dopamine D2 and D3 receptor antagonists.
Innovation Solution
Development of novel 1,3,8-triazinspiro[4,5]decane-4-ones compounds that act as dopamine D2 and D3 antagonists, specifically substituted at the N1, N3, or N8 positions, which can be used to treat various gastrointestinal disorders and nausea-related conditions by administering them alone or in combination with opioid analgesics.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current antiemetic drugs and gastric motility agents are used, then treatment of nausea and vomiting is provided, but efficacy is insufficient for PONV and gastroparesis
Solution Approach 1:
The patent applies parameter changes by modifying the chemical structure of dopamine receptor antagonists through systematic variation of substituents at N1, N3, and N8 positions of the 1,3,8-triazaspiro[4,5]decan-4-one core. This structural parameter optimization enables the compounds to achieve superior affinity and selectivity for dopamine D2 and D3 receptors, thereby resolving the insufficiency of current antiemetic drugs for treating PONV and gastroparesis
2Object-affected harmful factors
If conventional dopamine antagonists are used, then antiemetic effect is achieved, but side effects increase due to mu opioid receptor binding and CNS penetration
Solution Approach 1:
The patent applies local quality by designing compounds with specific substituent patterns at different positions (N1, N3, N8) of the triazaspiro core to achieve differential receptor interactions. The cyclohexyl group at N1 and specific acyl substituents at N3 or N8 provide localized structural features that enhance selectivity for dopamine D2/D3 receptors while minimizing interactions with mu opioid receptors and reducing CNS penetration, thus improving safety without sacrificing antiemetic efficacy
Data Source
AI summary
Provided are D2 or D3 antagonist compounds and pharmaceutical compositions of formula I and pharmaceutically acceptable salts thereof, or isomers thereof, wherein R1, R2 and R3 are as defined herein. The invention further comprises methods for making the compounds of the invention and methods for the treatment of conditions mediated by the dopamine D2 or D3 receptor from the compounds of the invention.