Sulfonamido HDAC Inhibitors Reducing P450 Affinity
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Solution Overview
Problem
Current histone deacetylase inhibitors lack high enzymatic activity, cellular activity, and bioavailability, and often have side effects, particularly interacting with P450 enzymes, which limits their therapeutic potential in treating proliferative diseases like cancer and psoriasis.
Innovation Solution
Development of novel compounds with specific structural features that exhibit excellent histone deacetylase inhibiting activity, high bioavailability, particularly oral bioavailability, and reduced affinity for P450 enzymes, thereby minimizing side effects and enhancing therapeutic efficacy.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If current histone deacetylase inhibitors are used, then some enzymatic activity is achieved, but high enzymatic activity, cellular activity, and bioavailability are not attained, and side effects occur particularly through P450 enzyme interactions
Solution Approach 1:
The patent applies parameter changes by systematically modifying molecular parameters of HDAC inhibitors, specifically changing the chemical structure from traditional hydroxamate groups to sulfonamido derivatives. This structural parameter change results in reduced affinity for P450 enzymes (resolving the harmful interaction) while maintaining or enhancing HDAC inhibitory activity through optimized molecular features such as aromatic rings, heterocyclic groups, and specific substituent patterns.
Solution Approach 2:
The patent applies local quality by introducing specific functional groups at particular positions within the molecular structure. The sulfonamido group is positioned to interact with the HDAC active site while avoiding P450 enzyme binding regions. Additional local modifications include specific substituents on aromatic rings and heterocyclic moieties that enhance cellular activity and bioavailability without increasing P450 affinity.
2Adaptability or versatility
If structural modifications are made to improve bioavailability and reduce P450 affinity, then therapeutic potential increases, but compound complexity increases
Solution Approach 1:
The patent manages complexity through controlled parameter changes, focusing on a core sulfonamido-benzene-heterocyclic scaffold with limited but strategic substituent variations. Rather than exploring vast chemical space, the invention optimizes specific parameters such as heterocyclic ring type (pyridine, pyrimidine, triazine), substituent position, and chain length to achieve the desired balance between bioavailability, P450 affinity, and structural simplicity.
Data Source
AI summary
This invention comprises the novel compounds of formula (I)wherein n, m, t, R1, R2, R3, R4, R5, L, Q, X, Y, Z andhave defined meanings, having histone deacetylase inhibiting enzymatic activity; their preparation, compositions containing them and their use as a medicine.