Substituted Quinazolines for Selective HDAC6 Inhibition
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Solution Overview
Problem
Existing HDAC6 inhibitors suffer from lack of selectivity, causing significant side-effects and poor pharmacokinetics, limiting their clinical effectiveness in treating diseases such as cancers and neurodegenerative disorders.
Innovation Solution
Development of highly selective HDAC6 inhibitors, represented by compounds of formula (I), which improve bioavailability, reduce side-effects, and enhance pharmacokinetics compared to hydroxamic acid-based inhibitors.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If hydroxamic acid-based HDAC6 inhibitors are used, then HDAC6 inhibition activity is achieved, but selectivity is poor causing significant side-effects
Solution Approach 1:
The patent applies local quality by modifying specific regions of the HDAC6 inhibitor molecule while maintaining the core hydroxamic acid functionality. The general formula (I) structure introduces specific substituent patterns at defined positions that enhance selectivity for HDAC6 over other HDAC isoforms, thereby reducing off-target side effects while preserving the desired enzymatic inhibition activity.
2Reliability
If hydroxamic acid-based HDAC6 inhibitors are used, then HDAC6 inhibition activity is achieved, but pharmacokinetics are poor limiting potency
Solution Approach 1:
The patent employs parameter changes by systematically varying chemical parameters such as substituent types, chain lengths, and molecular weight within the general formula (I) framework. These parameter modifications optimize the pharmacokinetic properties including absorption, distribution, metabolism, and excretion (ADME) characteristics, thereby improving overall potency and therapeutic effectiveness while maintaining HDAC6 inhibition activity.
3Productivity
If high doses of non-selective HDAC inhibitors are used, then therapeutic effect is enhanced, but toxicity increases causing fatigue and nausea
Solution Approach 1:
The patent applies partial action by designing inhibitors with selective affinity for HDAC6 rather than pan-HDAC inhibition. This selectivity allows achieving therapeutic effects at lower doses by specifically targeting HDAC6, thereby avoiding the toxicity and side effects (fatigue, nausea) associated with high-dose non-selective HDAC inhibitors that affect multiple HDAC isoforms.
4Reliability
If hydroxamic acid-based HDAC6 inhibitors are used, then HDAC6 inhibition is achieved, but bioavailability is low reducing effectiveness
Solution Approach 1:
The patent utilizes parameter changes by optimizing molecular parameters such as lipophilicity, molecular size, and hydrogen bonding capacity within the general formula (I) structure. These parameter adjustments enhance the oral bioavailability of HDAC6 inhibitors, ensuring sufficient drug concentration reaches the target site to achieve therapeutic effectiveness.
5Reliability
If hydroxamic acid-based HDAC6 inhibitors are used, then HDAC6 inhibition is achieved, but water-solubility is poor affecting drug delivery
Solution Approach 1:
The patent applies local quality by introducing polar substituents and hydrophilic groups at specific positions within the general formula (I) molecular structure. These localized modifications improve water solubility and aqueous solubility characteristics without compromising the core HDAC6 inhibition activity, thereby facilitating better drug delivery and formulation options.
Data Source
AI summary
The present invention relates to a compound of formula (I)or a pharmaceutically acceptable salt and/or solvate thereof,wherein Y1 is a 9- or 10-membered bicyclic heteroaryl, Y2 is a 5-membered heteroaryl, Z1 is selected from (C═O)—R9, S(O)—R9 and S(O2)—R9, L is an alkyl-, cycloalkyl- or heterocycloalkyl-based linker, and R1 and R9 may be various groups.The present invention further relates to a compound of formula (I) as HDAC6 inhibitor, typically for use in the treatment and/or the prevention of an HDAC6-associated disease, such as cancers, neurodegenerative diseases, neuropathies or cardiovascular diseases.