RORγ Modulators Targeting IL-17/IL-23 Axis
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Solution Overview
Problem
Current treatments for autoimmune and inflammatory diseases, such as psoriasis, multiple sclerosis, and rheumatoid arthritis, are inadequate in targeting the IL-17/IL-23 axis, which is crucial for TH17 cell regulation and inflammation.
Innovation Solution
Development of novel RORγ modulator compounds, specifically defined by Formula I, which inhibit RORγ activity to reduce IL-17 and IL-23-mediated pathogenic responses, thereby treating RORγ-mediated diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments for autoimmune and inflammatory diseases are used, then existing therapeutic options are available, but they are inadequate in targeting the IL-17/IL-23 axis
Solution Approach 1:
The patent develops novel chemical compounds with specific molecular structures (Formula I) that bind to and modulate RORγt protein function. By changing the chemical parameters of the ligand molecule, the treatment achieves specific targeting of the IL-17/IL-23 axis through RORγt inhibition, thereby improving both reliability and adaptability of the therapy
2Object-affected harmful factors
If RORγ activity is inhibited to reduce IL-17 and IL-23 expression, then pathogenic responses are reduced, but new compound development is required
Solution Approach 1:
The patent performs preliminary action by designing and synthesizing a series of candidate compounds according to Formula I before clinical application. The compounds are pre-optimized for RORγt binding affinity and selectivity, and pre-tested in experimental models to confirm efficacy in reducing IL-17 and IL-23 expression, thereby preparing effective treatments in advance
Solution Approach 2:
The patent systematically varies chemical parameters in the compounds of Formula I (such as substituents R1-R16, and core structure variations) to optimize binding to RORγt. This parameter optimization ensures high potency and selectivity, enabling effective inhibition of pathogenic responses while establishing a manufacturable compound class
Data Source
AI summary
The present invention relates to compounds according to Formula I: Wherein: A11 - A14 are N or CR11, CR12, CR13, CR14, respectively, with the proviso that no more than two of the four positions A can be simultaneously N; R1 is C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1 -3)alkyl, (di)C(1-6)alkylamino, (di)C(3-6)cycloalkylamino or (di)(C(3-6)cycloalkylC(1 -3)alkyl)amino, with all carbon atoms of alkyl groups optionally substituted with one or more F and all carbon atoms of cycloalkyl groups optionally substituted with one or more F or methyl; R2 and R3 are independently H, F, methyl, ethyl, hydroxy, methoxy or R2 and R3 together is carbonyl, all alkyl groups, if present, optionally being substituted with one or more F; R4 is H or C(1-6)alkyl; R5 is H, hydroxyethyl, methoxyethyl, C(1-6)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1 -9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1 -3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl, all groups optionally substituted with one or more F, CI, C(1-2)alkyl, C(1-2)alkoxy or cyano; the sulfonyl group with R1 is represented by one of R7, R8 or R9; the remaining R6-RH are independently H, halogen, C(1-3)alkoxy, (di)C(1-3)alkylamino or C(1-6)alkyl, all of the alkyl groups optionally being substituted with one or more F; and Ri5 and Ri6 are independently H, C(1-6)alkyl, C(3-6)cycloalkyl, C(3-6)cycloalkylC(1-3)alkyl, C(6-10)aryl, C(6-10)arylC(1-3)alkyl, C(1-9)heteroaryl, C(1-9)heteroarylC(1-3)alkyl, C(2-5)heterocycloalkyl or C(2-5)heterocycloalkylC(1-3)alkyl, all groups optionally substituted with one or more F, CI, C(1-2)alkyl, C(1-2)alkoxy or cyano. The compounds can be used as inhibitors of RORy and are useful for the treatment of RORy mediated diseases.