Sulfonyl CCR6 Inhibitors for Selective Chemokine Targeting
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Solution Overview
Problem
Current pharmacological interventions for chemokine receptor CCR6 are complicated due to its promiscuous interactions with multiple chemokines, making selective targeting challenging for inflammatory autoimmune diseases like psoriatic diseases, asthma, Crohn's disease, ulcerative colitis, rheumatoid arthritis, systemic lupus erythematosus, and multiple sclerosis.
Innovation Solution
Development of sulfonyl derivatives that act as selective CCR6 inhibitors, formulated as compounds of specific structural formulas to target and modulate CCR6 signaling, thereby reducing immune cell recruitment to inflamed tissues.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If pharmacological interventions target CCR6 receptor, then immune cell trafficking can be modulated for treating inflammatory diseases, but selectivity is reduced due to promiscuous interactions with multiple chemokines
Solution Approach 1:
The patent applies local quality by designing a highly specific ligand structure (sulfonyl derivative with specific substituents R1-R7) that targets only the CCR6 receptor binding site. The molecular structure is locally optimized with specific chemical groups positioned to interact uniquely with CCR6 amino acid residues, ensuring selective binding while avoiding cross-reactivity with other chemokine receptors.
Solution Approach 2:
The patent employs parameter changes by systematically varying the chemical parameters of the ligand molecule (substituents R1-R7 at different positions on the core structure) to optimize binding affinity and selectivity for CCR6. By adjusting these molecular parameters, the invention achieves high selectivity despite the receptor's promiscuous nature.
2Reliability
If selective CCR6 inhibitors are developed, then on-target pharmacology is achieved, but development complexity increases due to need for high selectivity
Solution Approach 1:
The patent applies preliminary action by conducting extensive in silico molecular modeling and in vitro binding assays during the drug discovery phase to pre-validate CCR6 selectivity before clinical development. This preliminary characterization of selectivity across multiple chemokine receptors reduces later development complexity by identifying potential off-target effects early in the process.
Solution Approach 2:
The patent uses computational chemistry tools and structure-activity relationship (SAR) analysis as intermediaries to guide the optimization of sulfonyl derivative structures. These intermediary methods allow virtual screening and prediction of selectivity, reducing the need for extensive empirical testing and simplifying the overall development process.
Data Source
AI summary
The present invention provides new derivatives having the general formula (I)wherein R1, R2, R3, R4, R5, R6, R7, X1, X2, X3, X4, and X5 are as defined herein, compositions including the compounds, processes of manufacturing the compounds and methods of using the compounds.