Biphenyl Triazol Compounds as Potent SOCE Modulators

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Solution Overview

Problem

Current therapies lack potent and selective modulators for Store-Operated Calcium Entry (SOCE), which is crucial for treating diseases associated with abnormal SOCE, particularly those caused by STIM1 and Orai1 mutations.

Innovation Solution

Development of biphenyl 1,4-disubstituted 1,2,3-triazol compounds that act as novel SOCE modulators, capable of regulating the activity of CRAC channels with high potency and specificity towards STIM1 and Orai1, thereby addressing the unmet need for effective treatment of related diseases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If existing SOCE modulators are used, then some inhibitory activity is achieved, but potency and selectivity are insufficient for effective treatment

Engineering Contradiction:

Improvepotency and selectivity of SOCE modulationVSAvoidlack of effective treatment options

Core Design Contradiction:

ReliabilityVSObject-generated harmful factors

Solution Approach 1:

The patent modifies molecular parameters of SOCE modulators by introducing biphenyl 1,4-disubstituted 1,2,3-triazol compounds with specific substituents (A1-A5, B1-B5, R1-R3) to achieve nanomolar IC50 values, representing a significant improvement in potency compared to existing modulators

Inventive Principle:

Principle #35Parameter changes

Solution Approach 2:

The invention creates composite molecular structures combining biphenyl cores with triazol rings and various functional groups (carboxylic acid, hydroxyl, amine, etc.) to achieve both high potency and selectivity for STIM1/Orai1 modulation

Inventive Principle:

Principle #40Composite materials

2Reliability

If potent SOCE modulators are developed, then treatment effectiveness improves, but cytotoxicity may increase

Engineering Contradiction:

Improvepotency of SOCE inhibitionVSAvoidcytotoxicity

Core Design Contradiction:

ReliabilityVSObject-affected harmful factors

Solution Approach 1:

The patent introduces specific local functional groups (carboxylic acid at position A1, hydroxyl at A2, amine at A3) on the biphenyl-triazol structure to achieve selective interaction with STIM1/Orai1 while maintaining low cytotoxicity through localized chemical properties

Inventive Principle:

Principle #3Local quality

3Reliability

If selective modulators for STIM1 and Orai1 are created, then treatment specificity improves, but compound complexity increases

Engineering Contradiction:

Improveselectivity towards STIM1 and Orai1VSAvoidstructural complexity of compounds

Core Design Contradiction:

ReliabilityVSDevice complexity

Solution Approach 1:

The patent divides the molecular structure into distinct functional segments: the biphenyl 1,4-disubstituted core (positions A1-A5), the triazol ring system (B1-B5), and the substituent groups (R1-R3), allowing selective optimization of each segment for STIM1/Orai1 interaction while maintaining manageable structural complexity

Inventive Principle:

Principle #1Segmentation

Data Source

PatentEP4106871B1Biphenyl compounds as SOCE modulators, compositions and uses thereof

Publication Date: 2024.03.13 UNIV DEGLI STUDI DEL PIEMONTE ORIENTALEAMEDEO AVOGADRO

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AI summary

Compound of formula (I) able to modulate Store Operated Calcium Entry (SOCE). The disclosure also relates to compositions and uses of compounds of formula (I) for treatment of disease condition depending on increased/ decreased activity of SOCE.