MRGPRX4 Modulator Compounds for Refractory Pruritus
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Solution Overview
Problem
Patients with liver conditions such as primary biliary cholangitis, primary sclerosing cholangitis, or progressive familial intrahepatic cholestasis suffer from refractory pruritus, which is severe and can lead to depression and suicidal thoughts, and existing small compounds for modulating MRGPRX4 activity have limitations.
Innovation Solution
Development of compounds with specific structures, such as those of formula I or their pharmaceutically acceptable salts, which act as MRGPRX4 modulators to prevent or treat conditions associated with MRGPRX4 activation, including pruritus, by administering these compounds alone or in combination with other therapeutic agents like FXR agonists.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing small compounds are used to modulate MRGPRX4 activity, then some therapeutic effect is achieved, but the treatment effectiveness is limited and pruritus remains refractory
Solution Approach 1:
The patent applies parameter changes by developing compounds with specific structural parameters (formula I with defined substituents R1-R17, ring systems A and B, and linkage Lra) to optimize MRGPRX4 modulation. The compounds feature specific molecular weight ranges, hydrophobicity values, and functional group configurations that enhance binding affinity and selectivity for MRGPRX4, thereby improving treatment effectiveness over existing compounds
Solution Approach 2:
The patent employs composite material principles by creating compounds that combine multiple functional moieties within a single molecular structure. The compounds integrate aromatic ring systems, linker regions, and terminal functional groups in a composite architecture that enables simultaneous interaction with MRGPRX4 binding sites, achieving superior modulatory effect compared to simpler compounds
2Reliability
If bile acids or MRGPRX4 agonists are administered to activate MRGPRX4, then itch-related responses are elicited, but this worsens pruritus symptoms in patients
Solution Approach 1:
The patent applies inversion by developing compounds that act as MRGPRX4 modulators with opposite effect to agonists. Instead of activating MRGPRX4 to elicit itch responses like bile acids and agonists do, the compounds modulate the receptor to suppress pruritus. The structural design targets the same receptor but produces inverted physiological outcomes, converting harmful activation into beneficial suppression
Data Source
AI summary
Among other things, the present disclosure provides compounds, e.g., of formula I or salts thereof. In some embodiments, the present disclosure provides methods for modulating MRGPRX4 activity. In some embodiments, the present disclosure provides methods for preventing or treating conditions, disorders or diseases, e.g., MRGPRX4-associated conditions, disorders or diseases.