Sulfoximine Glycosidase Inhibitors for Selective OGA Targeting
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Solution Overview
Problem
Current OGA inhibitors are non-selective, leading to concomitant inhibition of lysosomal β-hexosaminidases, and lack improved pharmacological properties, which is a challenge in developing effective treatments for diseases associated with tauopathies and Alzheimer's disease.
Innovation Solution
Development of novel low molecular weight compounds with a sulfoximine group that selectively inhibit OGA, reducing plasma protein binding and increasing the unbound fraction, thereby achieving higher unbound brain concentrations and improved metabolic stability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If non-selective OGA inhibitors are used, then inhibition of OGA is achieved, but lysosomal β-hexosaminidases are also inhibited causing harmful effects
Solution Approach 1:
The patent applies local quality by designing inhibitors with specific molecular features (aromatic rings, hydrogen bond donors/acceptors, specific spatial arrangement) that create localized interaction patterns with OGA's active site. These localized chemical properties enable selective binding to OGA while avoiding interaction with lysosomal hexosaminidases, thus achieving selective inhibition without harmful off-target effects.
Solution Approach 2:
The patent employs parameter changes by systematically varying molecular parameters of the inhibitors including aromatic ring substitution patterns, hydrogen bond donor/acceptor positions, and molecular weight. These parameter optimizations tune the inhibitors' affinity and selectivity for OGA, achieving potent inhibition (IC50 values in nanomolar range) while maintaining selectivity against other glycosidases.
2Reliability
If conventional OGA inhibitors are used, then OGA activity is inhibited, but plasma protein binding is high reducing unbound fraction
Solution Approach 1:
The patent applies parameter changes by optimizing molecular weight, lipophilicity, and hydrogen bonding capacity of the inhibitors. These parameter adjustments reduce plasma protein binding affinity while maintaining OGA inhibition potency, thereby increasing the unbound fraction available for therapeutic action and improving pharmacokinetic properties.
3Reliability
If high molecular weight compounds are used, then OGA inhibition potency is achieved, but metabolic stability decreases and dosing requirements increase
Solution Approach 1:
The patent employs parameter changes by optimizing molecular weight to a specific range and adjusting metabolic stability parameters through structural modifications. These changes achieve potent OGA inhibition while enhancing resistance to metabolic degradation, thereby extending duration of action and reducing dosing frequency without sacrificing potency.
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 compounds demonstrate increased metabolic stability and higher unbound fractions in plasma, leading to enhanced efficacy and reduced dosing requirements for treating neurodegenerative diseases, including tauopathies and Alzheimer's, without inhibiting lysosomal hexosaminidases.
Implementation Method 1
a nonselective N-acetylglucosaminidase inhibitor was used to increase tau O-GlcNAc levels
Implementation Method 2
reducing plasma protein binding and increasing the unbound fraction
Implementation Method 3
leading to enhanced efficacy and reduced dosing requirements for treating neurodegenerative diseases
Data Source
AI summary
Compounds of formula (I) wherein A, R, W1, W2, W3, W4, W5, W6, L, Q, Rx and u have the meaning according to the claims can be employed, inter alia, for the treatment of tauopathies and Alzheimer's disease.