Selective OX1R Antagonists for Impulse Control Disorders
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Solution Overview
Problem
Current dual orexin receptor antagonists are not suitable for treating disorders related to impulse control deficits, such as addictions and eating disorders, due to their sleep-inducing effects, making it desirable to have an orexin receptor type 1 (OX1R) selective antagonist.
Innovation Solution
Development of novel N-[(Pyrimidinylamino)propanyl]- and N-[(Pyrazinylamino)-propanyl]arylcarboxamide derivatives that act as highly potent and selective OX1R antagonists with improved stability in human liver microsomes and reduced MDCK efflux, enhancing their pharmacodynamic and pharmacokinetic properties.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If dual orexin receptor antagonists (OX1R and OX2R) are used, then sleep-inducing effects are achieved, but the compounds are not suitable for treating impulse control deficits
Solution Approach 1:
The patent segments the orexin receptor antagonism function by designing compounds that selectively target only OX1R while excluding OX2R. This is achieved through specific molecular structure design (formula I) that creates steric and electronic complementarity only with OX1R binding site, thereby separating the therapeutic effect (impulse control) from the side effect (sleep induction) associated with dual antagonism
Solution Approach 2:
The invention applies local quality by introducing specific substituents at defined positions in the molecular structure (R1-R6 groups in formula I) that confer OX1R selectivity. The heteroaryl group (pyrimidinyl, pyrazinyl) at specific positions and the arylcarboxamide moiety create localized interactions with OX1R that are absent in OX2R, enabling selective antagonism for impulse control disorders without sedative effects
2Adaptability or versatility
If OX1R selective antagonists are developed, then impulse control disorder treatment is enabled, but metabolic stability and pharmacokinetic properties need improvement
Solution Approach 1:
The patent employs parameter changes by systematically varying molecular parameters such as heteroaryl substitution patterns (pyrimidinyl vs pyrazinyl), aryl group types, and carboxamide configurations to optimize both OX1R selectivity and metabolic stability. The specific structural parameters in formula I are tuned to resist cytochrome P450 metabolism while maintaining pharmacological activity, achieving improved half-life and reliability for clinical use
Data Source
AI summary
The present invention relates to novel N-[(Pyrimidinylamino)propanyl]- and N-[(Pyrazinylamino)-propanyl]arylcarboxamide derivatives, processes for their preparation, pharmaceutical compositions containing them and their use in therapy, particularly in the treatment or prevention of conditions having an association with the orexin sub-type 1 receptor.