Bis-Adenosine Tetraphosphate Antiplatelet Agents
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Solution Overview
Problem
Current antiplatelet agents, such as clopidogrel, have limitations including delayed action, significant inter-patient variability, and prolonged antithrombotic effects, which can lead to increased bleeding risks and drug-drug interactions, necessitating the development of fast-acting and reversible antiplatelet agents.
Innovation Solution
Development of symmetrical and asymmetrical bis-adenosine tetraphosphate compounds with specific functional groups that inhibit ADP-induced platelet aggregation, providing a pharmaceutical composition for nasal inhalation and parenteral administration to effectively inhibit platelet aggregation in both in vitro and in vivo settings.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Speed
If clopidogrel is used as an antiplatelet agent, then platelet aggregation is inhibited, but the action is delayed and requires preloading patients before procedures
Solution Approach 1:
The patent extracts and eliminates the prodrug requirement by designing adenosine tetraphosphate compounds that are directly active without needing metabolic activation by cytochrome P450 enzymes, thereby removing the delay inherent in clopidogrel's mechanism
Solution Approach 2:
The patent changes the chemical structure parameters by using adenosine tetraphosphate backbone instead of thienopyridine, which fundamentally alters the pharmacokinetic profile to achieve rapid onset without metabolic conversion
2Reliability
If clopidogrel is used for long term prophylactic use, then cardiovascular events are reduced, but the antithrombotic effect persists long after administration increasing bleeding risk
Solution Approach 1:
The patent implements periodic/reversible action through adenosine tetraphosphate compounds that produce transient platelet inhibition without irreversible binding, allowing the effect to wear off and enabling safer perioperative management
Solution Approach 2:
The patent enables recovery of platelet function by using reversible inhibitors that are naturally eliminated without requiring irreversible covalent bonding to platelet receptors, allowing platelets to regain full function after drug clearance
3Productivity
If clopidogrel is metabolized by cytochrome P450 enzymes, then active metabolite is produced, but significant inter-patient variability occurs due to variations in P450 system and liver function
Solution Approach 1:
The patent removes the dependency on cytochrome P450 metabolic pathway by designing compounds that are directly active in their administered form, eliminating the source of inter-patient variability associated with P450 polymorphisms and liver function differences
Solution Approach 2:
The patent creates a simplified version of the antiplatelet mechanism that copies the desired therapeutic effect without the complex metabolic activation step, using adenosine tetraphosphate structures that directly interact with platelet receptors
4Reliability
If clopidogrel irreversibly inhibits P2Y12 platelet receptors, then antithrombotic activity is achieved, but drug-drug interactions increase due to liver metabolism requirements
Solution Approach 1:
The patent extracts and eliminates the liver metabolism requirement by using adenosine tetraphosphate compounds that do not depend on cytochrome P450 enzymes for activation, thereby removing the primary source of drug-drug interactions
Solution Approach 2:
The patent inverts the conventional approach by using reversible inhibition instead of irreversible inhibition, and direct action instead of metabolic activation, fundamentally changing the interaction profile with other medications
Data Source
AI summary
The invention features compounds of formula I and methods of their use as antiplatelet and antithrombotic compounds: H/N=Qχ2OOOOΛQ2-N, HR6/NIf)(^XMO-MγτOM°τX1MQ′)r(^rfHOOHHOOQHiNχiR2 Formula (I).