N-Desulfated Heparin Derivatives for Selective Heparanase Inhibition
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Solution Overview
Problem
Current therapies for multiple myeloma and other tumors lack effective heparanase inhibitors with high selectivity and bioavailability, as existing compounds often have significant anticoagulant activity or limited efficacy.
Innovation Solution
Development of N-desulfated and optionally 2-O-desulfated glycosaminoglycan derivatives, where adjacent diols and OH/NH2 groups are converted to aldehydes and then reduced to alcohols, specifically targeting heparanase inhibition with reduced anticoagulant activity and enhanced bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing heparanase inhibitor compounds are used, then heparanase inhibition activity is achieved, but anticoagulant activity and side effects increase
Solution Approach 1:
The patent applies parameter changes by chemically modifying the sulfation degree and molecular weight of heparin derivatives. Specifically, N-desulfated heparin and low sulfated heparin derivatives are used to reduce anticoagulant activity while maintaining heparanase inhibition. The sulfation degree is reduced to less than 50%, preferably less than 20%, thereby changing the chemical parameters to achieve selective inhibition with reduced side effects
Solution Approach 2:
The patent applies local quality by creating heterogeneous populations of glycosaminoglycan chains with different sulfation patterns. The heparin derivatives contain chains with varying degrees of N-desulfation and O-desulfation, creating local regions with different functional properties. This allows certain chains to selectively inhibit heparanase while others maintain minimal anticoagulant activity
2Reliability
If high molecular weight heparin is used for heparanase inhibition, then inhibition efficacy is improved, but bioavailability and pharmacokinetic properties deteriorate
Solution Approach 1:
The patent applies segmentation by breaking down high molecular weight heparin into lower molecular weight fragments and oligosaccharides. The heparin derivatives have molecular weights ranging from 1,000 to 10,000 Da, with many chains being oligosaccharides of 3-15 disaccharide units. This segmentation improves bioavailability and pharmacokinetic properties while maintaining heparanase inhibition capability
Solution Approach 2:
The patent changes the molecular weight parameter from high (unfractionated heparin) to low (1,000-10,000 Da), thereby improving absorption, distribution, and elimination characteristics. The reduced molecular weight allows better tissue penetration and longer circulation half-life, directly addressing the bioavailability issue
3Reliability
If conventional heparin derivatives are used, then anticoagulant effect is achieved, but selectivity for heparanase inhibition and therapeutic index worsen
Solution Approach 1:
The patent applies parameter changes by precisely controlling the sulfation degree (less than 50%, preferably less than 20%) and molecular weight (1,000-10,000 Da) of the heparin derivatives. These parameter changes create a selective profile that favors heparanase inhibition over anticoagulant activity, thereby improving the therapeutic index
Solution Approach 2:
The patent creates simplified copies of the natural heparin-heparanase interaction by using shorter oligosaccharide chains (3-15 disaccharide units) that retain the key binding motifs for heparanase inhibition. These copied structures maintain the essential functional groups while removing unnecessary complexity that contributes to anticoagulant activity
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 novel glycosaminoglycan derivatives demonstrate strong heparanase inhibitory activity, both in vitro and in vivo, showing improved efficacy in treating myeloma and other tumors with reduced side effects and increased bioavailability compared to existing compounds.
Implementation Method 1
adjacent diols and OH/NH2 have been converted into the corresponding aldehyde
Implementation Method 2
aldehydes have been then reduced to the corresponding alcohol
Data Source
AI summary
A glycosaminoglycan derivative which is obtainable by a process that includes the steps of N-desulfation of from 25% to 100% of the N-sulfated residues of a glycosaminoglycan, and oxidation, by periodate at a pH of from 5.5 to 10.0, of from 25% to 100% of the 2-N-, 3-O-non-sulfated glucosamine residues, and of the 2-O-non-sulfated uronic acid residues of said glycosaminoglycan, under conditions effective to convert adjacent diols and adjacent OH/NH2 to aldehydes. The process further includes reduction, by sodium borohydride, of said oxidized glycosaminoglycan, under conditions effective to convert said aldehydes to alcohols, where the glycosaminoglycan is heparin, low molecular weight heparin, heparan sulfate or fractions thereof.