Indazole PD-1/PD-L1 Modulators With Improved Drug-Like Properties
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing compounds for blocking or inhibiting PD-1/PD-L1 interactions lack improved physicochemical, pharmacological, and pharmaceutical properties, limiting their effectiveness in treating cancer.
Innovation Solution
Development of 1,4-diphenyl-1H-indazole and 1-pyridin-2-yl-4-phenyl-1H-indazole derivatives that modulate PD-1 activity, PD-L1 activity, or the PD-1/PD-L1 interaction, offering enhanced properties for cancer treatment.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If monoclonal antibodies are used to block PD-1/PD-L1 interactions, then immune response is restored and tumor rejection is enhanced, but the compounds lack improved physicochemical, pharmacological and pharmaceutical properties
Solution Approach 1:
The patent applies parameter changes by developing small molecule compounds with optimized physicochemical properties (molecular weight, logP, solubility, metabolic stability) while maintaining PD-1/PD-L1 blocking activity. The indazole derivatives are designed with specific structural parameters (aromatic rings, heteroatoms, substituent patterns) to achieve improved pharmacokinetic and pharmacodynamic profiles compared to existing monoclonal antibodies
Solution Approach 2:
The patent substitutes the large protein-based monoclonal antibody mechanism with a small molecule chemical mechanism. Instead of using antibody-antigen recognition, the invention employs small molecule ligands that bind to PD-1 or PD-L1, replacing the biological macromolecule system with a simplified chemical system that offers improved drug-like properties
2Reliability
If existing compounds are used for PD-1/PD-L1 blockade, then cancer treatment is achieved, but pharmacological properties are not improved
Solution Approach 1:
The patent applies dynamics by designing compounds with optimized metabolic stability and half-life characteristics. The indazole derivatives are structured to achieve appropriate duration of action through controlled metabolism and clearance, allowing for dosing regimens that maintain therapeutic levels while avoiding toxicity, thus improving upon the pharmacological duration profile of existing agents
3Reliability
If existing compounds are used for PD-1/PD-L1 inhibition, then immune response is enhanced, but pharmaceutical properties are not improved
Solution Approach 1:
The patent applies segmentation by dividing the complex therapeutic function into manageable structural components within the small molecule framework. The indazole core is segmented with specific substituents (aromatic rings, heteroatoms, functional groups) that can be independently optimized for synthesis, purification, and formulation, making the compounds easier to manufacture with improved pharmaceutical properties compared to monoclonal antibodies
Data Source
AI summary
The present disclosure relates to compounds of Formula (I):and to their prodrugs, pharmaceutically acceptable salts, pharmaceutical compositions, methods of use, and methods for their preparation. The compounds disclosed herein are useful for modulating PD-1 activity, PD-L1 activity, and/or the PD-1/PD-L1 interaction and may be used in the treatment of disorders in which PD-1 activity, PD-L1 activity, and/or PD-1/PD-L1 interaction is implicated, such as cancer.