Indane-Amine PD-L1 Antagonists for Oral Bioavailability and Stability
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Solution Overview
Problem
There is a need for alternative small molecules as inhibitors of PD-L1 that offer advantages in oral administration, stability, bioavailability, therapeutic index, and toxicity compared to existing PD-1 pathway inhibitors.
Innovation Solution
Development of indane-amine compounds with specific structural formulas (I) and their pharmaceutically acceptable salts, which can be used in pharmaceutical compositions for therapeutic methods targeting the PD-1/PD-L1 pathway.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Ease of operation
If conventional PD-1 pathway inhibitors (antibodies) are used, then immune checkpoint blockade activity is achieved, but oral administration is not feasible and bioavailability is limited
Solution Approach 1:
The patent replaces the mechanical/injectable antibody-based PD-1 pathway inhibitors with small molecule compounds that can be administered orally. The small molecules bind to PD-L1 and prevent its interaction with PD-1, achieving the same immunological effect through a different delivery mechanism that enables oral administration and improves bioavailability.
2Ease of operation
If existing small molecule PD-L1 inhibitors are developed, then oral administration is enabled, but stability and therapeutic index are insufficient
Solution Approach 1:
The patent systematically modifies chemical parameters of the small molecule compounds, including introducing specific functional groups (carboxylic acid, hydroxyl, amino), adjusting molecular weight, and optimizing structural features to enhance metabolic stability and pharmacokinetic properties while maintaining PD-L1 binding activity.
3Ease of operation
If existing small molecule PD-L1 inhibitors are developed, then oral administration is enabled, but toxicity increases and therapeutic index decreases
Solution Approach 1:
The patent introduces specific functional groups and structural features at particular locations in the molecule to enhance selectivity for PD-L1 binding. This localized optimization ensures that the compound's active sites are precisely positioned to interact with the target protein, reducing off-target effects and minimizing toxicity while maintaining therapeutic efficacy.
Data Source
AI summary
Compounds are provided that are useful as immunomodulators. The compounds have the Formula (I) including stereoisomers and pharmaceutically acceptable salts thereof, wherein R1, R2a, R2b, R2c, R3, R4, R5, R6a, R6b, m and n are as defined herein. Methods associated with preparation and use of such compounds, as well as pharmaceutical compositions comprising such compounds, are also disclosed.