Selective HDAC Inhibitors via Structural Modification
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Solution Overview
Problem
Current HDAC inhibitors are non-selective, affecting all HDAC isoforms, and there is a need to identify compounds that specifically inhibit certain HDAC isoforms, such as HDAC-4, HDAC-5, HDAC-6, HDAC-7, HDAC-8, HDAC-9, and HDAC-11, to modulate histone deacetylase activity for therapeutic applications in diseases like cancer and inflammation.
Innovation Solution
Development of novel compounds represented by Formulas (II) and (XX), including N-oxides, hydrates, solvates, and pharmaceutically acceptable salts, which are designed to selectively inhibit specific HDAC isoforms, allowing for targeted modulation of histone deacetylase activity.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If known HDAC inhibitors are used, then HDAC activity is inhibited, but all HDAC isoforms are affected non-selectively
Solution Approach 1:
The patent applies local quality by designing HDAC inhibitors with specific structural modifications at particular positions of the molecule to achieve selective inhibition of certain HDAC isoforms. The compound structure includes specific substituents (R1-R6, R9-R12) that can be tailored to interact with unique features of target HDAC isoforms, allowing differential binding affinity and selectivity among HDAC family members.
Solution Approach 2:
The patent employs parameter changes by systematically varying chemical parameters such as substituent types, positions, and configurations in the HDAC inhibitor molecules. By changing these chemical parameters, the patent achieves different selectivity profiles for various HDAC isoforms while maintaining inhibitory activity, thus resolving the contradiction between effectiveness and selectivity.
2Reliability
If non-selective HDAC inhibitors are used, then broad HDAC activity is suppressed, but specific therapeutic modulation of certain isoforms is not achieved
Solution Approach 1:
The patent applies segmentation by dividing the HDAC inhibitor development into different classes (Class I, II, and III inhibitors) with distinct structural features. Each class targets specific HDAC isoforms differently, allowing for precise therapeutic modulation. The segmented approach enables selection of appropriate inhibitor classes based on the specific disease indication and target isoform.
Solution Approach 2:
The patent uses local quality by incorporating specific functional groups and structural motifs at defined positions in the inhibitor molecules to achieve isoform-specific binding. The detailed structural definitions (Formulas I and II with specific substituent options) enable precise targeting of particular HDAC isoforms, improving therapeutic precision.
Data Source
AI summary
This invention relates to compounds for the inhibition of histone deacetylase. More particularly, the invention provides for compounds of formula compounds of the Formula (I) and N-oxides, hydrates, solvates, pharmaceutically acceptable salts, prodrugs and complexes thereof, and racemic and scalemic mixtures, diastereomers and enantiomers thereof, wherein groups L, M, X and Y are as defined herein.