1,3,4-Oxadiazole HDAC6 Inhibitors With Reduced Off-Target Toxicity
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Solution Overview
Problem
Current HDAC inhibitors, particularly non-selective ones, cause side effects such as fatigue and nausea due to their broad activity across HDAC classes, limiting their use in treating diseases beyond cancer, while selective HDAC6 inhibitors with improved bioavailability and reduced side effects are needed for conditions like cancer, inflammatory diseases, autoimmune diseases, and neurodegenerative disorders.
Innovation Solution
Development of 1,3,4-oxadiazole derivative compounds with selective HDAC6 inhibitory activity, including optical isomers and pharmaceutically acceptable salts, which are designed to target HDAC6 and treat associated diseases.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-selective HDAC inhibitors are used to achieve broad anticancer activity, then cancer cell death is induced, 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 compounds that selectively target specific HDAC isoforms (Class IIa and Class IIb) rather than inhibiting all HDACs non-selectively. This segmentation allows for targeted therapy that achieves anticancer activity while avoiding the side effects associated with broad-spectrum HDAC inhibition, particularly the fatigue and nausea caused by Class I HDAC inhibition.
Solution Approach 2:
The patent applies local quality by designing HDAC inhibitors with specific molecular structures that confer selectivity for particular HDAC isoforms. By modifying the cap group, linker, and zinc-binding group to match specific HDAC isoform characteristics, the compounds achieve localized inhibition of target isoforms (Class IIa/IIb) while sparing other HDACs, thereby reducing off-target side effects.
2Object-affected harmful factors
If selective Class II HDAC inhibitors are developed to reduce toxicity, then side effects from non-selective inhibition are solved, but the inhibitors must achieve sufficient potency and bioavailability for therapeutic use
Solution Approach 1:
The invention employs parameter changes by systematically modifying key molecular parameters of the HDAC inhibitor structure, including the cap group (aromatic or heteroaromatic rings), linker (ethylene diamine, propylene diamine, or piperazine derivatives), and zinc-binding group (hydroxamic acid, carboxylic acid, or amide). These parameter modifications optimize both selectivity for Class II HDACs and therapeutic efficacy while maintaining reduced toxicity.
Solution Approach 2:
The patent creates composite molecular structures by combining specific cap groups, linkers, and zinc-binding groups into unified HDAC inhibitor molecules. These composite structures integrate multiple functional elements that work synergistically to achieve selective Class II HDAC inhibition with sufficient potency and bioavailability for therapeutic application.
Data Source
AI summary
The present invention relates to a novel compound having a histone deacetylase 6 (HDAC6) inhibitory activity, an isomer thereof or a pharmaceutically acceptable salt thereof, the use thereof for preparing a therapeutic medicament; a pharmaceutical composition containing the same, and a treatment method using the composition; and a preparation method thereof. The novel compound, the isomer thereof, or the pharmaceutically acceptable salt thereof according to the present invention has the HDAC6 inhibitory activity, which is effective in the prevention or treatment of HDAC6-mediated diseases including cancer, inflammatory diseases, autoimmune diseases, neurological or neurodegenerative diseases.