Non-peptide Macrocyclic HDAC Inhibitors for Oral Bioavailability
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Solution Overview
Problem
Current cyclic-peptide HDAC inhibitors face challenges due to poor oral bioavailability and limited in vivo efficacy, primarily because of their peptide backbone, which hampers membrane penetration and offers limited opportunities for side-chain modifications, thus requiring the development of non-peptide macrocyclic HDAC inhibitors with improved pharmacokinetic properties for therapeutic applications.
Innovation Solution
Development of non-peptide macrocyclic HDAC inhibitors featuring a macrolide subunit with a zinc-binding group, a linking group, and a spacer, which can be administered as free acids or salts, and formulated for various administration routes, including enteral, parenteral, and topical, to enhance bioavailability and tissue targeting.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If cyclic-peptide HDAC inhibitors are used, then HDAC inhibitory activity is achieved, but oral bioavailability and membrane penetration are poor
Solution Approach 1:
The patent changes the chemical parameters of the inhibitor by replacing the peptide backbone with a non-peptide macrocyclic structure. This structural parameter change maintains HDAC inhibitory activity while improving membrane penetration and oral bioavailability by eliminating the polar amide bonds characteristic of peptides.
Solution Approach 2:
The invention creates a composite molecular structure combining a macrocyclic core with zinc-binding groups and hydrophobic linkers. This composite approach integrates the functions of different molecular components to achieve both potent HDAC inhibition and improved pharmacokinetic properties.
2Reliability
If cyclic-peptide HDAC inhibitors are used, then HDAC inhibitory activity is achieved, but opportunities for side-chain modifications are limited
Solution Approach 1:
The patent segments the inhibitor into distinct functional modules: a macrocyclic core, zinc-binding groups, and interchangeable linkers and caps. This segmentation allows independent optimization of each module and facilitates diverse combinatorial modifications to explore structure-activity relationships and improve selectivity.
Solution Approach 2:
The macrocyclic scaffold serves as a universal platform that can accommodate multiple different zinc-binding groups and cap structures. This multi-functional design enables the same core structure to be adapted for targeting different HDAC isoforms with varying selectivity profiles.
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 new class of non-peptide macrocyclic HDAC inhibitors demonstrates improved efficacy and targeted delivery, potentially offering potent anti-cancer, anti-inflammatory, and anti-parasitic activities with enhanced bioavailability and selectivity, overcoming the limitations of existing cyclic-peptide inhibitors.
Implementation Method 1
a zinc-binding group (ZBG)
Data Source
AI summary
Compounds of Formula I or II, and methods of making and using thereof, are described herein.M represents a macrolide subunit,E is a C1-6 group, optionally containing one or more heteroatoms,D is an alkyl or aryl group,A is a linking group connected to D,B is an alkyl, alkylaryl or alkylheteroaryl spacer group,ZBG is a Zinc Binding Group,R1, R2 and R4 are independently are selected from hydrogen, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, a C1-6 alkanoate group, a C2-6 carbamate group, a C2-6 carbonate group, a C2-6 carbamate group, or a C2-6 thiocarbamate group,R3 is hydrogen or —OR5,R5 is selected from a group consisting of Hydrogen, a C1-6 alkyl group, a C2-6 alkenyl group, a C2-6 alkynyl group, C1-6 alkanoate group, C2-6 carbamate group, C2-6 carbonate group, C2-6 carbamate group, or C2-6 thiocarbamate group.