OX1R Selective Benzamides for Impulse Control
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current orexin receptor antagonists, particularly dual OX1R and OX2R antagonists, are not suitable for treating impulse control deficits in disorders like addiction and eating disorders due to their sleep-inducing effects, and there is a need for an OX1R selective antagonist to address these conditions effectively.
Innovation Solution
Development of novel N-[(pyrazinyloxy)propanyl]benzamide derivatives that act as potent and selective OX1R antagonists with enhanced stability in human liver microsomes, providing improved pharmacodynamic and pharmacokinetic properties, including increased selectivity over OX2R and longer duration of action.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If dual OX1R and OX2R antagonists are used, then sleep-inducing effects are achieved, but impulse control deficits cannot be treated
Solution Approach 1:
The invention segments the orexin receptor antagonism function by designing a compound that selectively targets only the OX1R receptor subtype while excluding OX2R. This segmentation allows the drug to treat impulse control deficits through OX1R antagonism without causing the harmful sleep-inducing effects associated with OX2R antagonism, thereby resolving the technical contradiction between therapeutic efficacy and side effects
Solution Approach 2:
The patent applies local quality by modifying the molecular structure to create specific interactions with the OX1R receptor binding site. The N-[(pyrazinyloxy)propanyl]benzamide core structure with specific substituents (R1, R2, R3, and Ar groups) is designed to fit the OX1R binding pocket geometry and chemistry, providing selective antagonism at this specific receptor location while leaving OX2R unaffected, thus achieving local specificity to avoid systemic side effects
2Reliability
If OX1R selective antagonists are developed, then impulse control deficits can be treated, but stability in human liver microsomes may be reduced
Solution Approach 1:
The patent employs parameter changes by systematically varying the substituents on the benzamide core structure (R1 = hydrogen, fluoro, or methyl; R2 = hydrogen, fluoro, chloro, methyl, -CF3, or -OCH3; R3 = hydrogen, fluoro, or -CF3; Ar = various aromatic groups). These parameter modifications allow optimization of both selectivity parameters (OX2R/OX1R ratio) and stability parameters (half-life in human liver microsomes) simultaneously, resolving the contradiction between achieving high selectivity and maintaining metabolic stability
Data Source
AI summary
This invention relates to compounds of formula (I) a process for their preparation, pharmaceutical compositions containing them and their use in the treatment of conditions having an association with the orexin sub-type 1 receptor. Ar, R1, R2 and R3 have meanings given in the description.