Selective ROR Modulators via Sulfonamide and Carboxamide Derivatives
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Current technologies lack effective modulators for retinoic acid receptor-related orphan receptors (RORs), which are crucial for treating metabolic, immune, and CNS disorders, as existing ligands often have off-target effects on other nuclear receptors and cellular components.
Innovation Solution
Development of sulfonamides and carboxamide derivatives as selective ROR modulators, including agonists, repressors, and antagonists, that specifically target RORα, RORβ, and RORγ without affecting LXRα and LXRβ, thereby minimizing side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing ligands are used to modulate ROR activity, then ROR modulation is achieved, but off-target effects on other nuclear receptors and cellular components occur
Solution Approach 1:
The patent applies local quality by designing ligands with specific structural features (sulfonamide and carboxamide groups at particular positions on the steroid backbone) that confer selectivity for ROR over other nuclear receptors. The modifications are localized to specific regions of the molecule to achieve differential binding affinity.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters of the ligand structure, including substitution patterns at positions 2, 3, and 17 of the steroid backbone, and the nature of the substituent groups (sulfonamide, carboxamide, hydroxyl). These parameter variations optimize both ROR binding affinity and selectivity.
2Adaptability or versatility
If broad-spectrum nuclear receptor modulators are used, then multiple receptor targets are affected, but therapeutic selectivity is reduced
Solution Approach 1:
The patent achieves therapeutic selectivity through local quality by introducing specific functional groups (sulfonamide at position 3, carboxamide at position 17) that create a unique binding profile for ROR receptors while minimizing interaction with other nuclear receptors like LXR and FXR.
3Reliability
If high-affinity ROR ligands are developed, then ROR binding is enhanced, but cross-reactivity with similar nuclear receptors increases
Solution Approach 1:
The patent resolves the affinity-selectivity tradeoff through parameter changes by optimizing the steroid backbone substitutions, particularly the introduction of sulfonamide and carboxamide groups with specific stereochemistry and positioning, which enhance ROR binding while maintaining discrimination against cross-reactivity.
Data Source
AI summary
The invention provides small molecule modulators of retinoic acid receptor-related orphan receptors such as RORα, RORβ, or RORγ, of formulawith the variable atoms as defined herein and R1 comprising a hydroxyl- or alkoxyl-substituted fluoroalkyl group. Compounds of the invention can be effective modulators at concentrations ineffective to act on LXR receptors, or on other nuclear receptors, or other biological targets. Methods of modulation the RORs and methods of treating metabolic disorders, immune disorders, cancer, and CNS disorders wherein modulation of an ROR is medically indicated are also provided.