SOC Channel Modulators via STIM1 Binding
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Solution Overview
Problem
Current technologies fail to effectively modulate store-operated calcium (SOC) channel activity, which is crucial for regulating various cellular functions, including cell proliferation, gene transcription, and cytokine release, as existing compounds do not adequately inhibit SOC or calcium-release activated calcium (CRAC) channels.
Innovation Solution
Development of compounds of Formula (I), (II), (IIA), or (IIB) that selectively inhibit SOC or CRAC channel activity by interacting with proteins such as STIM1 and STIM2, thereby modulating intracellular calcium levels and channel activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing compounds are used to modulate SOC channel activity, then some level of calcium modulation is achieved, but the inhibition of SOC or CRAC channels is inadequate
Solution Approach 1:
The patent modifies chemical parameters of the compounds by varying substituents at specific positions (R1-R6 groups) to optimize the balance between inhibition efficacy and structural complexity. Different substituent combinations allow tuning of the compound's affinity for SOC/CRAC channels while maintaining manageable structural complexity.
Solution Approach 2:
The compounds represent composite molecular structures combining multiple functional groups (thiophene or pyridine core, amide linkers, aromatic substituents) that work synergistically to achieve effective SOC/CRAC channel inhibition. The composite nature of these molecules allows simultaneous optimization of binding affinity and pharmacological properties.
2Reliability
If SOC channel activity is strongly inhibited, then cytokine expression and cell proliferation are reduced, but selectivity against other calcium channels may be compromised
Solution Approach 1:
The compounds exhibit local quality through specific substituent patterns that enhance binding affinity for SOC/CRAC channels while maintaining selectivity. The thiophene or pyridine core with specific R1-R6 substituents creates a molecular architecture that preferentially interacts with SOC channel proteins, allowing strong inhibition without affecting other calcium channel types.
Solution Approach 2:
The patent employs partial action by designing compounds that achieve sufficient inhibition of SOC channels at specific concentration ranges, avoiding excessive inhibition that might lead to off-target effects. The dose-dependent nature of these compounds allows selective modulation of SOC channels while preserving other physiological calcium signaling pathways.
Data Source
AI summary
Described herein are compounds and pharmaceutical compositions containing compounds of Formula (I), which modulate the activity of store-operated calcium (SOC) channels:wherein R1, R2 and R4 are defined herein. Also described herein are methods of using such SOC channel modulators, alone and in combination with other compounds, for treating diseases or conditions that would benefit from inhibition of SOC channel activity.