Triazole Compounds Targeting GABA A α5 Receptors
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Solution Overview
Problem
Current benzodiazepine receptor inverse agonists, while enhancing spatial learning, are proconvulsant and non-selective, limiting their use as cognition-enhancing agents due to potential seizure-inducing effects and lack of specificity for GABA A α5 subunits, which are linked to various CNS disorders.
Innovation Solution
Development of triazole compounds with high affinity and selectivity for the GABA A α5 receptor, functioning as inverse agonists to treat or prevent neurological disorders and cognitive impairments without the proconvulsant activity of conventional benzodiazepine receptor inverse agonists.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If conventional benzodiazepine receptor inverse agonists are used to enhance spatial learning, then cognition is improved, but proconvulsant activity and lack of selectivity occur
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (triazole core with particular substituents) that confer selectivity for the α5 subunit. The chemical structure is locally optimized at specific positions (R1, R2, R3 groups) to interact preferentially with α5 receptor binding sites while avoiding α1, α2, and α3 subunits, thereby achieving cognition enhancement without proconvulsant effects.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters (substituent types, positions, and configurations on the triazole ring) to modulate receptor selectivity. By changing molecular parameters such as the nature of R1 (aryl, heteroaryl), R2 (alkyl, aryl), and R3 (halo, cyano, alkyl) groups, the compounds achieve optimal balance between cognitive enhancement efficacy and safety profile free from proconvulsant activity.
2Reliability
If conventional benzodiazepine receptor inverse agonists are used, then spatial learning is enhanced, but selectivity for GABA A α5 subunits is lacking
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (triazole core with particular substituents) that confer selectivity for the α5 subunit. The chemical structure is locally optimized at specific positions (R1, R2, R3 groups) to interact preferentially with α5 receptor binding sites while avoiding α1, α2, and α3 subunits, thereby achieving cognition enhancement without proconvulsant effects.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters (substituent types, positions, and configurations on the triazole ring) to modulate receptor selectivity. By changing molecular parameters such as the nature of R1 (aryl, heteroaryl), R2 (alkyl, aryl), and R3 (halo, cyano, alkyl) groups, the compounds achieve optimal balance between cognitive enhancement efficacy and safety profile free from proconvulsant activity.
Data Source
AI summary
The present invention is concerned with novel triazole compounds of formula (I)wherein A, X, Y, u, v, R1, R2, and R3 are as described herein, as well as pharmaceutically acceptable salts thereof. The compounds of present invention have affinity and selectivity for the GABA A α5 receptor. Further the present invention is concerned with the manufacture of the compounds of formula (I), pharmaceutical compositions comprising them and their use as pharmaceuticals.