S1P1 Receptor Modulators via Heterocyclic Segmentation
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Solution Overview
Problem
Current treatments for multiple sclerosis, transplant rejection, and adult respiratory distress syndrome lack effective sphingosine-1-phosphate receptor subtype 1 (S1P1) agonists or antagonists that selectively target S1P1 receptors with high specificity and efficacy.
Innovation Solution
Development of heterocyclic compounds, such as those of formula 265, which act as selective agonists or antagonists for S1P1 receptors, formulated into pharmaceutical compositions for administration in various forms to treat conditions mediated by S1P1 activation or inhibition, including multiple sclerosis, transplant rejection, and adult respiratory distress syndrome.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current treatments are used for multiple sclerosis, transplant rejection, and adult respiratory distress syndrome, then existing therapeutic options are available, but effective S1P1 receptor agonists or antagonists with high specificity and efficacy are lacking
Solution Approach 1:
The patent applies local quality by designing heterocyclic compounds with specific structural features (oxadiazole or oxazole rings combined with heteroaryl groups) that confer selective affinity for S1P1 receptors over other sphingosine-1-phosphate receptor subtypes. This localized structural optimization enables the compounds to interact preferentially with S1P1 receptors, achieving both high efficacy and receptor selectivity for treating multiple sclerosis, transplant rejection, and adult respiratory distress syndrome
Solution Approach 2:
The patent employs parameter changes by systematically modifying molecular parameters of the heterocyclic compounds, including variations in heteroaryl groups, substituent patterns, and molecular configuration. These parameter adjustments optimize the balance between S1P1 receptor binding affinity and selectivity, producing compounds that effectively target S1P1 receptors while minimizing off-target effects on other receptor subtypes
2Ease of operation
If S1P1 receptor agonists are developed to treat multiple sclerosis, transplant rejection, and adult respiratory distress syndrome, then therapeutic benefits are achieved, but selective targeting of S1P1 receptors with high specificity remains challenging
Solution Approach 1:
The patent applies segmentation by dividing the sphingosine-1-phosphate receptor ligand class into distinct heterocyclic compound series with specific structural motifs. The compounds are segmented into those containing oxadiazole rings versus oxazole rings, each with characteristic binding properties. This segmentation allows for precise tuning of receptor selectivity while maintaining therapeutic efficacy across different indications including multiple sclerosis, transplant rejection, and adult respiratory distress syndrome
Data Source
Figure 1A~1B
Figure 1C
Figure 2
AI summary
Compounds that activate a sphingosine-1-phosphate receptor of the subtype 1 are provided. Certain compounds selectively activate the receptor subtype 1 in relation to the sphinogosine-1-phosphate receptor subtype 3. Uses and methods of inventive compounds for treatment of malconditions wherein activation, agonism, inhibition or antagonism of the S1P1 is medically indicated are provided.