RORγ Modulators Reducing Cardiac Safety Risks
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Solution Overview
Problem
Current RORγ modulators lack improved safety profiles, posing risks in the treatment of autoimmune and inflammatory diseases due to potential cardiac safety issues and drug-drug interactions.
Innovation Solution
Development of novel RORγ modulator compounds, specifically 2-{4-[(cyclopropylmethyl)sulfonyl]phenyl}-N-{4-[(1R)- or (1S)- (difluoromethyl)-2,2,2-trifluoro-1-hydroxyethyl}phenyl}acetamide, and their pharmaceutically acceptable salts, which inhibit RORγ activity with improved safety profiles by minimizing hERG channel inhibition and CYP3A4 inhibition.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing RORγ modulators are used to treat autoimmune and inflammatory diseases, then therapeutic efficacy is achieved, but cardiac safety risks and drug-drug interactions increase
Solution Approach 1:
The patent modifies the chemical structure of RORγ modulators by changing specific molecular parameters - introducing a cyclopropylmethylsulfonyl group at the 4-position of the phenyl ring and a specific hydroxyethyl group with fluorine atoms. These structural parameter changes result in compounds that maintain therapeutic efficacy while reducing hERG channel inhibition and CYP3A4 inhibition, thereby improving safety profile and reducing cardiac safety risks and drug-drug interactions
Solution Approach 2:
The patent creates composite molecular structures by combining specific functional groups - the cyclopropylmethylsulfonyl group, the phenyl ring, the hydroxyethyl group with fluorine atoms, and the acetamide linkage. This composite molecular design achieves optimal balance between binding affinity to RORγ and safety properties, reducing harmful effects while maintaining therapeutic benefit
Data Source
AI summary
The present application relates to compounds according to (Formula IA) or (Formula IB):or a pharmaceutically acceptable salt thereof.The compounds can be used as inhibitors of RORγ and are useful for the treatment of RORγ mediated diseases.