Oxadiazole Amine Derivatives for Selective HDAC6 Inhibition
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Solution Overview
Problem
Current HDAC inhibitors, particularly non-selective ones, cause side effects like fatigue and nausea due to their broad inhibition of HDACs, limiting their use beyond cancer treatment, and existing zinc-binding groups in HDAC inhibitors suffer from low bioavailability and off-target toxicity.
Innovation Solution
Development of oxadiazole amine derivative compounds with selective HDAC6 inhibitory activity, which are designed to minimize side effects and improve bioavailability by modifying the zinc-binding group, thereby targeting HDAC6 for various diseases without affecting other HDAC classes.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Adaptability or versatility
If non-selective HDAC inhibitors are used, then broad HDAC inhibition is achieved, but side effects such as fatigue and nausea occur due to inhibition of class I HDACs
Solution Approach 1:
The invention segments the HDAC inhibitor market by developing selective inhibitors for specific HDAC classes (Class I, IIa, IIb, IV) rather than using non-selective inhibitors. This allows targeted inhibition of specific HDAC isoforms responsible for therapeutic effects while avoiding inhibition of HDACs causing side effects, thereby resolving the contradiction between broad inhibition and side effect avoidance
Solution Approach 2:
The patent applies local quality by designing inhibitors with specific structural characteristics tailored to bind particular HDAC isoforms. By modifying the cap group, linker, and zinc-binding group to match specific HDAC active site features, the inhibitor achieves selective binding to target HDACs while sparing other isoforms, thus maintaining therapeutic efficacy without causing side effects
2Reliability
If zinc-binding groups in HDAC inhibitors are used, then enzyme inhibitory activity is achieved, but low bioavailability and off-target toxicity occur
Solution Approach 1:
The invention changes the chemical parameters of the zinc-binding group by exploring various alternatives (hydroxamic acid, benzamide, carboxylate, isothiazolone, oxadiazole) with different molecular properties. This allows optimization of the balance between zinc-binding affinity (for HDAC inhibition) and pharmacokinetic properties (bioavailability and selectivity), thereby maintaining enzyme inhibitory activity while reducing off-target toxicity
3Object-affected harmful factors
If selective HDAC inhibitors are developed, then side effects from non-selective inhibition are overcome, but development complexity increases
Solution Approach 1:
The patent employs local quality by designing inhibitors with specific structural characteristics tailored to bind particular HDAC isoforms. By modifying the cap group, linker, and zinc-binding group to match specific HDAC active site features, the inhibitor achieves selective binding to target HDACs while sparing other isoforms, thus maintaining therapeutic efficacy without causing side effects
Solution Approach 2:
The invention applies universality by developing a modular inhibitor design platform where the cap group, linker, and zinc-binding group can be systematically varied to target different HDAC isoforms. This multi-functional approach allows a single chemical framework to be adapted for selective inhibition of multiple HDAC classes, reducing overall development complexity through reuse of successful structural motifs
Applied Scientific Principles
This section explains which scientific principles are used to turn an abstract innovation direction into a practical engineering solution.
Function Achieved in This Case
The oxadiazole amine derivatives effectively inhibit HDAC6 activity, offering a therapeutic option for diseases like cancer, inflammatory, autoimmune, neurological disorders, and neurodegenerative diseases with reduced side effects and improved bioavailability.
Implementation Method 1
11 HDACs use zinc as a cofactor... the zinc-binding group is known to play a more important role in enzyme inhibitory activity and selectivity
Data Source
AI summary
The present disclosure relates to novel compounds having histone deacetylase 6 (HDAC6) inhibitory activity, stereoisomers thereof or pharmaceutically acceptable salts thereof, the use thereof for the preparation of therapeutic medicaments, pharmaceutical compositions containing the same, a method for treating diseases using the composition, and methods for preparing the novel compounds. The novel compounds, stereoisomers thereof or pharmaceutically acceptable salts thereof according to the present disclosure have histone deacetylase (HDAC) inhibitory activity and are effective for the prevention or treatment of HDAC6-mediated diseases, including infectious diseases; neoplasms; endocrine, nutritional and metabolic diseases; mental and behavioral disorders; neurological diseases; diseases of the eye and adnexa; cardiovascular diseases; respiratory diseases; digestive diseases; diseases of the skin and subcutaneous tissue; diseases of the musculoskeletal system and connective tissue; or congenital malformations, deformations and chromosomal abnormalities.