Macrocyclic FKBP51 Ligands Balancing Affinity and Drug Properties
Find Innovative SolutionsGenerate Solutions
Solution Overview
Problem
Existing FKBP inhibitors exhibit sub-optimal physicochemical and pharmacokinetic characteristics, leading to reduced selectivity and affinity for target molecules, and there is a need for compounds that can efficiently inhibit FKBP51 with lower molecular weights and lipophilicity.
Innovation Solution
Development of macrocyclic FKBP51-binding compounds with specific substituents and pharmaceutically acceptable salts, which enhance affinity and selectivity while reducing molecular weight and lipophilicity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing FKBP inhibitors are used, then FKBP51 inhibition is achieved, but physicochemical and pharmacokinetic characteristics are sub-optimal
Solution Approach 1:
The patent applies parameter changes by modifying the molecular structure of FKBP inhibitors to achieve optimal physicochemical and pharmacokinetic characteristics. Specific changes include adjusting molecular weight, lipophilicity, and structural parameters to improve drug properties while maintaining FKBP51 inhibition efficiency.
Solution Approach 2:
The patent employs composite materials by creating macrocyclic compounds that combine multiple functional features. These macrocyclic structures integrate rigid and flexible moieties, along with specific substituents, to achieve both high affinity binding and improved pharmacokinetic properties simultaneously.
2Ease of manufacture
If FKBP inhibitors are modified to improve characteristics, then physicochemical properties are enhanced, but selectivity and affinity for target molecule are reduced
Solution Approach 1:
The patent applies local quality by making specific modifications at particular positions within the macrocyclic structure. Different regions of the molecule are optimized independently - some areas are designed for high affinity binding while others are tuned for improved pharmacokinetics, maintaining overall selectivity and affinity.
Solution Approach 2:
The patent employs segmentation by dividing the macrocyclic structure into distinct functional modules. These segments can be independently optimized for different purposes - binding affinity, selectivity, and pharmacokinetic properties - while maintaining the overall integrity of the inhibitor molecule.
3Ease of manufacture
If molecular weight and lipophilicity are reduced, then pharmacokinetic characteristics are improved, but binding affinity may be compromised
Solution Approach 1:
The patent applies spheroidality by utilizing macrocyclic structures with curved or ring-like geometries. These curved structures provide efficient binding surfaces for FKBP51 while maintaining compact molecular sizes and optimal lipophilicity, achieving both high affinity and improved pharmacokinetics.
Solution Approach 2:
The patent employs nested doll by incorporating smaller functional groups within the macrocyclic structure. These nested substituents and moieties contribute to binding affinity while the overall macrocyclic framework maintains controlled molecular weight and lipophilicity levels.
Data Source
AI summary
The present invention relates to macrocyclic FKBP51-binding compounds having improved characteristics, as well as solvates, hydrates and/or pharmaceutically acceptable salts of these compounds as well as pharmaceutical compositions containing at least one of these compounds together with pharmaceutically acceptable carrier, excipient and/or diluents. Said compounds have been identified as especially potent ligands of FK506 binding proteins (FKBPs also called MIPs in bacteria), especially human FKBP51 and are useful for treatment of diseases such as psychiatric, metabolic and neurological disorders as well as pain and cancers. Said substituted derivatives may further be used as agents for inducing protein-protein interactions (PPIs) acting as molecular glues (FIG. 10).