Novel Antiplatelet Compounds for Consistent Platelet Inhibition
Find Innovative SolutionsGenerate Solutions
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, including Formula (I) and their pharmaceutically acceptable salts, which can inhibit platelet aggregation and are administered to treat vascular diseases.
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 CYP2C19 expression levels
Solution Approach 1:
The patent modifies the chemical structure of clopidogrel by replacing the oxazole ring with isoxazole or triazole rings, and adjusting substituent groups to create compounds with improved metabolic stability and reduced dependence on CYP2C19 polymorphism, thereby achieving more consistent antithrombotic efficacy across different patients
Solution Approach 2:
The patent develops compound 1b as a prodrug that combines a clopidogrel core structure with modified side chains, creating a composite molecular structure that undergoes predictable biotransformation to yield active metabolites with reduced interpatient variability
2Reliability
If clopidogrel is administered to achieve adequate antiplatelet effect, then a high loading dose (600 mg) is required, but this results in slow onset of action (2 h after loading dose)
Solution Approach 1:
The patent modifies molecular parameters of clopidogrel derivatives to improve solubility and bioavailability, enabling faster absorption and conversion to active metabolites, thereby reducing the onset of action time while maintaining adequate antiplatelet effects at lower doses
Solution Approach 2:
The patent designs prodrugs that are pre-configured for rapid biotransformation into active metabolites upon administration, eliminating the need for high loading doses and achieving fast onset of action within minutes rather than hours
3Reliability
If clopidogrel is used for treatment, then platelet aggregation inhibition is achieved, but low solubility in aqueous solution prevents injection formulation for acute treatment
Solution Approach 1:
The patent introduces polar substituents and modifies molecular polarity of clopidogrel derivatives to significantly improve aqueous solubility, enabling the development of injectable formulations for acute treatment while preserving antiplatelet activity
Solution Approach 2:
The patent employs solubilizing groups and prodrug designs that act as intermediaries to enhance water solubility without compromising the core antiplatelet mechanism, allowing parenteral administration for urgent clinical scenarios
4Reliability
If clopidogrel undergoes two-step oxidation via CYP2C19 to become active, then the active thiol-metabolite binds P2Y12 receptor, but drug-drug interactions occur due to enzyme involvement
Solution Approach 1:
The patent alters the metabolic pathway by modifying the oxazole ring to isoxazole or triazole rings, changing the enzymatic processing requirements and reducing dependence on CYP2C19, thereby minimizing drug-drug interactions while maintaining reliable active metabolite formation through alternative metabolic routes
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.