Ester-Modified Antiplatelet Compounds Targeting CYP2C19 Variability
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Solution Overview
Problem
Clopidogrel, a widely used antithrombotic drug, suffers from interpatient variability, clopidogrel resistance, low conversion rate to active metabolite, slow onset of action, low solubility, and lack of an injection formulation for acute treatment, necessitating the development of improved compounds for inhibiting platelet aggregation.
Innovation Solution
Development of novel compounds with specific chemical structures, such as those described by Formula (I), which inhibit platelet aggregation and are administered to treat vascular diseases, offering improved efficacy and solubility compared to clopidogrel.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If clopidogrel is used as an antithrombotic drug, then platelet aggregation can be inhibited, but interpatient variability and clopidogrel resistance occur due to different expression levels of CYP2C19
Solution Approach 1:
The patent modifies the chemical structure of clopidogrel by changing the ester group at the 5-position to different substituents (such as methyl, ethyl, isopropyl groups), which alters the metabolic pathway and reduces dependence on CYP2C19 enzyme expression levels, thereby improving consistency of antithrombotic effects across different patients
Solution Approach 2:
The patent creates analog compounds with combined structural features that optimize both pharmacological activity and metabolic stability, integrating multiple functional groups that work synergistically to reduce interpatient variability while maintaining antiplatelet efficacy
2Reliability
If clopidogrel is administered to achieve adequate antiplatelet effect, then a high loading dose (600 mg) is required, but this increases the risk of side effects and drug-drug interactions
Solution Approach 1:
The patent modifies the chemical structure to improve conversion efficiency to active metabolite, allowing achievement of therapeutic antiplatelet effects at lower doses, thereby reducing the risk of side effects and drug-drug interactions associated with high loading doses
Solution Approach 2:
The patent creates analog compounds that replicate and optimize the pharmacological activity of clopidogrel while eliminating its metabolic limitations, producing compounds with better safety profiles at equivalent or lower doses
3Speed
If clopidogrel is used for acute treatment, then oral administration is required, but this is insufficient for acute settings where rapid onset and injection formulation are needed
Solution Approach 1:
The patent modifies the chemical structure to improve aqueous solubility and pharmacokinetic properties, enabling formulation as injectable preparations that can be administered intravenously or intramuscularly for rapid onset in acute settings, while maintaining effectiveness for oral administration in chronic management
4Reliability
If clopidogrel is administered, then platelet aggregation inhibition is achieved, but the conversion rate to active metabolite is low, requiring high loading doses
Solution Approach 1:
The patent changes the chemical structure by modifying the ester group and other substituents to create compounds with improved metabolic stability and higher conversion rates to active metabolites through alternative metabolic pathways, reducing dependence on CYP2C19 enzyme activity
Data Source
AI summary
The present disclosure relates to compounds which exhibit activity in the inhibition of platelet aggregation as well as pharmaceutical compositions comprising these compounds and methods of treatment of vascular diseases by administration of these compounds or the pharmaceutical compositions.