Pyrazole Derivatives Modulating CRAC Channels for NSCLC Treatment
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Solution Overview
Problem
Current CRAC channel modulators lack sufficient potency and selectivity over voltage-operated calcium channels, and existing treatments for non-small cell lung cancer (NSCLC) are limited, with a need for more targeted and less invasive therapies.
Innovation Solution
Development of compounds of formula (I) and their pharmaceutically acceptable salts, which are calcium release-activated calcium channel modulators, specifically targeting CRAC channels to treat NSCLC by inhibiting calcium influx into cancer cells expressing ORAI or STIM proteins.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If CRAC channel modulators are developed to treat inflammatory diseases, then anti-inflammatory efficacy is improved, but selectivity over voltage-operated calcium channels deteriorates leading to adverse events in nervous and cardiovascular systems
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (Formula I) that target CRAC channels with high selectivity. The compounds feature specific substituents (R1-R6, Ar1-Ar3, X, Y, Z) that are optimized to interact selectively with CRAC channel binding sites, ensuring anti-inflammatory efficacy while avoiding voltage-operated calcium channels in the nervous and cardiovascular systems.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters of the compounds (different substituents, ring structures, and molecular configurations in Formula I) to optimize the balance between CRAC channel selectivity and potency. This allows tuning of the compounds to achieve therapeutic efficacy while minimizing off-target effects on other calcium channels.
2Reliability
If existing CRAC channel modulators are used, then some calcium channel modulation is achieved, but potency and selectivity over voltage-operated calcium channels are insufficient
Solution Approach 1:
The patent applies local quality by designing compounds with specific molecular structures (Formula I) that target CRAC channels with high selectivity. The compounds feature specific substituents (R1-R6, Ar1-Ar3, X, Y, Z) that are optimized to interact selectively with CRAC channel binding sites, ensuring anti-inflammatory efficacy while avoiding voltage-operated calcium channels in the nervous and cardiovascular systems.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters of the compounds (different substituents, ring structures, and molecular configurations in Formula I) to optimize the balance between CRAC channel selectivity and potency. This allows tuning of the compounds to achieve therapeutic efficacy while minimizing off-target effects on other calcium channels.
3Object-generated harmful factors
If conventional cancer treatments are used for NSCLC, then cancer cell destruction is achieved, but invasiveness and side effects increase
Solution Approach 1:
The patent applies the taking out principle by extracting and targeting a specific molecular mechanism (CRAC channel-mediated calcium influx) that is essential for cancer cell survival and proliferation. By selectively inhibiting this specific pathway in cancer cells expressing ORAI or STIM proteins, the treatment achieves cancer cell destruction while avoiding the non-specific toxicity and invasiveness of conventional chemotherapy approaches.
Solution Approach 2:
The patent employs the intermediary principle by using CRAC channel modulators as a mediator to disrupt the calcium signaling pathway in cancer cells. The compounds act as intermediaries that block the interaction between ORAI channels and STIM proteins, thereby preventing calcium influx and inducing cancer cell death through apoptosis, while sparing normal cells that do not rely as heavily on this pathway.
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The compounds effectively modulate CRAC channels, reducing calcium influx and inhibiting cancer cell proliferation, offering a potential therapeutic approach for NSCLC with improved specificity and reduced side effects.
Implementation Method 1
The compounds effectively modulate CRAC channels, reducing calcium influx and inhibiting cancer cell proliferation
Data Source
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AI summary
Disclosed are novel calcium release-activated calcium (CRAC) channel inhibitors, methods for preparing them, pharmaceutical compositions containing them, and methods of treatment using them. The present disclosure also relates to methods for treating non-small cell lung cancer (NSCLC) with CRAC inhibitors, and to methods for identifying therapeutics for treating and of diagnosing cancer.