Bicyclic Pyrazole Derivatives Target Slo-1 Channels
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Solution Overview
Problem
The growing problem of anthelmintic resistance in veterinary and human medicine, particularly against nematodes, necessitates the development of new compounds with improved anthelmintic activity and a broad spectrum of efficacy without adverse toxic effects.
Innovation Solution
The development of new bicyclic pyrazole derivatives that interact with Slo-1 channels in nematodes, leading to paralysis and inhibition, effectively treating gastrointestinal and extra-intestinal helminth infections.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing anthelmintics are used to control nematodes, then anthelmintic activity is achieved, but resistance develops leading to loss of efficacy
Solution Approach 1:
The patent develops compounds with a novel molecular structure (bicyclic pyrazole derivatives with specific substituents R1-R6) that represent a fundamental parameter change from existing anthelmintic classes. This structural innovation provides a new mode of action targeting Slo-1 calcium channels, bypassing resistance mechanisms that have developed against conventional anthelmintics
Solution Approach 2:
The invention introduces an intermediary mechanism by targeting a specific biological target (Slo-1 calcium channel) that mediates the anthelmintic effect. This specific targeting approach provides a novel pathway for action that is distinct from existing drugs, allowing the compounds to overcome resistance while maintaining efficacy
2Reliability
If macrocyclic lactones are used for heartworm prevention, then protection is achieved, but resistance develops in high challenge areas
Solution Approach 1:
The patent employs a parameter change by using bicyclic pyrazole derivatives with a completely different molecular scaffold from macrocyclic lactones. The compounds feature specific structural elements (pyrazole ring system with particular substituent patterns) that enable a novel mode of action against filarial nematodes, circumventing resistance to existing heartworm preventives
3Reliability
If new anthelmintic compounds are developed, then resistance-breaking activity is achieved, but toxic effects may increase
Solution Approach 1:
The patent applies local quality by designing compounds with specific substituent patterns (R1-R6 groups) that are positioned at particular locations on the molecular scaffold. This localized structural optimization allows the drug to selectively interact with the Slo-1 channel in nematodes while minimizing off-target effects on mammalian systems, achieving both efficacy and safety
Solution Approach 2:
The invention uses parameter changes by systematically varying molecular parameters (substituent types, positions, and configurations) to optimize the balance between anthelmintic activity and toxicity. The specific structural parameters of the bicyclic pyrazole core are tuned to achieve selective toxicity against nematodes while preserving safety for the host
Data Source
AI summary
The present invention covers bicyclic pyrazole compounds of general formula (I) : in which G, A, R1, R2, R3, and Q are as defined herein, methods of preparing said compounds, intermediate compounds useful for preparing said compounds, pharmaceutical compositions and combinations comprising said compounds and the use of said compounds for manufacturing pharmaceutical compositions for the treatment, control and/or prevention of diseases, in particular of helminth infections, as a sole agent or in combination with other active ingredients.