Selective HDAC6 Inhibitors for Proliferative Disease Treatment
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Solution Overview
Problem
Current treatments for proliferative diseases, such as cancer and cardiovascular diseases, lack effective HDAC6 inhibitors that can selectively target HDAC6 without causing broad histone deacetylase inhibition, which is crucial for minimizing side effects and maximizing therapeutic benefits.
Innovation Solution
Development of novel compounds represented by formulas (I), (II-A), and (II-B) that act as selective HDAC6 inhibitors, specifically designed to target HDAC6 with minimal impact on other histone deacetylases, thereby providing therapeutic benefits for proliferative diseases while minimizing side effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If broad histone deacetylase inhibition is used to treat proliferative diseases, then therapeutic benefits are achieved, but side effects increase due to lack of selectivity
Solution Approach 1:
The patent segments the histone deacetylase enzyme family by developing compounds that specifically inhibit HDAC6 while sparing other HDAC isoforms. This selective inhibition strategy divides the therapeutic effect into targeted action on HDAC6 versus non-targeted effects on other HDACs, thereby achieving therapeutic benefits while minimizing side effects associated with broad inhibition
Solution Approach 2:
The invention applies local quality by designing compounds with specific molecular structures (formulas I, II-A, and II-B) that exhibit preferential binding affinity for HDAC6's zinc-binding site compared to other HDAC isoforms. This localized selectivity ensures that the inhibitory effect is concentrated on HDAC6 while other HDACs remain functionally active, reducing off-target side effects
2Object-affected harmful factors
If selective HDAC6 inhibition is achieved through novel compound structures, then side effects are minimized, but compound complexity increases
Solution Approach 1:
The patent employs parameter changes by systematically modifying molecular parameters such as substituent groups (R1-R6), ring structures, and stereochemical configurations in compounds of formulas I, II-A, and II-B. These parameter variations are optimized to enhance selectivity for HDAC6 while maintaining manageable structural complexity and synthetic feasibility
Data Source
AI summary
This invention provides compounds of formula (/): wherein R1, R2, G, m, n, p and q have values as described in the specification, useful as inhibitors of HDAC6. The invention also provides pharmaceutical compositions comprising the compounds of the invention and methods of using the compositions in the treatment of proliferative, inflammatory, infectious, neurological or cardiovascular diseases or disorders.