Localized Deuterated Sabizabulin Composition for Predictable Pharmacokinetics
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Solution Overview
Problem
The pharmacokinetic properties of Sabizabulin, a tubulin inhibitor, are unpredictable and can be adversely affected by deuterium substitution, potentially shortening its half-life and increasing side effects, which complicates its use in treating malignant tumors and COVID-19 infection.
Innovation Solution
A deuterated Sabizabulin compound, represented by specific structural formulas, is developed to improve metabolic stability and pharmacokinetics, including various pharmaceutically acceptable salts, hydrates, and solvates, suitable for treating cancer, COVID-19, influenza, and respiratory distress syndrome.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Stability of the object's composition
If deuterium substitution is performed on Sabizabulin, then metabolic stability is improved, but pharmacokinetic properties become unpredictable and half-life may be shortened
Solution Approach 1:
The patent applies deuteration at specific local positions (R1-R17) rather than uniform substitution throughout the molecule. This localized approach allows optimization of metabolic stability at specific sites while maintaining predictable pharmacokinetic properties overall.
Solution Approach 2:
The patent systematically varies the deuteration pattern by selecting different combinations of R1-R17 positions for deuterium substitution. This parameter optimization approach identifies the specific deuteration pattern that achieves both improved metabolic stability and predictable pharmacokinetics.
2Duration of action of stationary object
If deuterium substitution is performed on Sabizabulin, then half-life is extended, but side effects increase
Solution Approach 1:
The patent targets specific local positions (R1-R17) for deuteration that are most likely to extend half-life through C-D bond stability, while avoiding positions where deuteration would generate harmful metabolic byproducts or increase side effects.
Solution Approach 2:
The patent converts the potential harm of unpredictable pharmacokinetics into benefit by systematically identifying deuteration patterns that achieve extended half-life through stable C-D bonds while maintaining predictable and favorable pharmacokinetic profiles.
3Stability of the object's composition
If hydrogen atoms are substituted with deuterium, then C-D bond stability increases, but steric hindrance prevents substitution at certain positions
Solution Approach 1:
The patent identifies specific local positions (R1-R17) where deuteration is both feasible and beneficial, avoiding positions with high steric hindrance while targeting positions where C-D bond formation is chemically accessible and metabolically advantageous.
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 deuterated Sabizabulin compound exhibits enhanced metabolic stability and pharmacokinetics, demonstrating improved half-life and reduced side effects, with potential for better therapeutic efficacy in cancer and infectious disease treatments.
Implementation Method 1
Deuterated drugs refer to the substitution of some hydrogens in drug molecules with deuterium. Since the stability of the C-D bond is better compared to the C—H bond, deuterated drugs are less likely to break the C-D bond during chemical reactions
Data Source
AI summary
A compound represented by formula (I) or an optical isomer, a pharmaceutically acceptable salt, a hydrate or a solvate thereof are provided. In formula (I), R1-R17 are each independently selected from hydrogen and deuterium, R18 and R19 are hydrogen, and R1-R19 are not simultaneously hydrogen. The deuterated compound and the salt, hydrate or solvate thereof have excellent metabolic stability and pharmacokinetic properties, and can be used in the manufacture of tubulin inhibitors, anti-cancer drugs, antiviral drugs, and drugs for the treatment of novel coronavirus pneumonia.