Substituted Bicyclic Compounds for Selective S1P1 Agonism

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Solution Overview

Problem

There is a need for compounds that act as selective S1P1 agonists to modulate lymphocyte migration, particularly for treating autoimmune and vascular diseases, while avoiding non-selectivity towards S1P3 receptors.

Innovation Solution

Development of substituted bicyclic compounds, including those of Formulas (I), (II), (III), and (IV), which are designed to selectively activate S1P1 receptors, thereby modulating lymphocyte trafficking and potentially treating autoimmune and vascular diseases.

Engineering Contradictions & Design Principles

VSEngineering Contradiction Analysis

1Reliability

If compounds are designed to activate S1P1 receptors, then lymphocyte trafficking is modulated, but non-selectivity towards S1P3 receptors occurs

Engineering Contradiction:

ImproveselectivityVSAvoidreceptor activation

Core Design Contradiction:

ReliabilityVSAdaptability or versatility

Solution Approach 1:

The patent applies local quality by introducing specific substituent groups at defined positions on the bicyclic core structure. Different substituents (R1-R6) are placed at specific locations to create localized interactions with S1P1 receptor binding sites, enhancing selectivity while maintaining overall receptor activation capability

Inventive Principle:

Principle #3Local quality

Solution Approach 2:

The patent employs parameter changes by systematically varying chemical parameters such as substituent types, chain lengths, and molecular weight within the bicyclic compound structure. These parameter modifications allow optimization of the balance between S1P1 selectivity and S1P3 cross-reactivity, enabling fine-tuned receptor activation profiles

Inventive Principle:

Principle #35Parameter changes

2Object-affected harmful factors

If substituted bicyclic compounds are developed for S1P1 selectivity, then side effects are reduced, but compound complexity increases

Engineering Contradiction:

Improveside effectsVSAvoidcompound structure

Core Design Contradiction:

Object-affected harmful factorsVSDevice complexity

Solution Approach 1:

The patent applies segmentation by dividing the bicyclic compound into distinct functional modules: a core bicyclic structure and separate substituent groups (R1-R6). This modular approach allows independent optimization of each segment for selectivity while managing overall molecular complexity through systematic variation of individual components

Inventive Principle:

Principle #1Segmentation

Solution Approach 2:

The patent employs universality by designing a versatile bicyclic core structure that can accommodate multiple different substituent combinations. This universal scaffold provides a foundation for generating multiple analogs with varying selectivity profiles, reducing side effects while maintaining manageable structural complexity through a consistent core framework

Inventive Principle:

Principle #6Universality (Multi-functionality)

Data Source

PatentUS11701373B2Substituted bicyclic compounds

Publication Date: 2023.07.18 BRISTOL MYERS SQUIBB CO

AI summary

Disclosed are compounds of Formulas (I), (II), (III), (IV), and (V):and/or a salt thereof, wherein R1 is —OH or —OP(O)(OH)2, and X1, X2, X3, R2, R2a, Ra, Rb, and Rc are defined herein. Also disclosed are methods of using such compounds as selective agonists for G protein-coupled receptor S1P1, and pharmaceutical compositions comprising such compounds. These compounds are useful in treating, preventing, or slowing the progression of diseases or disorders in a variety of therapeutic areas, such as autoimmune diseases and vascular disease.