Human Plasma Kallikrein Inhibitors for Controlled Thrombin Generation
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Solution Overview
Problem
Existing fibrinolytic therapies for acute myocardial infarction induce a hypercoagulable state, leading to increased thrombin generation, reocclusion of clots, and a heightened risk of intracranial hemorrhage, necessitating an adjunctive anticoagulant that inhibits thrombin formation without increasing bleeding risk.
Innovation Solution
Development of compounds that inhibit human plasma kallikrein to balance fibrinolysis/thrombosis, promoting clot dissolution and preventing reformation, using specific chemical structures represented by various formulas incorporating aryl or heteroaryl groups with varying substituents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Productivity
If fibrinolytic therapy is used to treat acute myocardial infarction, then clot dissolution is promoted, but a hypercoagulable state is induced leading to increased thrombin generation and reocclusion risk
Solution Approach 1:
The patent introduces plasma kallikrein inhibitors as intermediary substances that mediate between fibrinolytic therapy and the coagulation system. These inhibitors prevent the activation of the contact activation pathway, thereby controlling thrombin generation and preventing reocclusion while maintaining clot dissolution benefits
Solution Approach 2:
The patent changes the parameter of kallikrein activity by using specific inhibitors (such as HHA, HHA-NO2, and related compounds) that alter the biochemical pathway. This modifies the coagulation state from hypercoagulable to a balanced state, reducing thrombin generation without compromising fibrinolysis
2Productivity
If fibrinolytic therapy is used to treat acute myocardial infarction, then clot dissolution is promoted, but intracranial hemorrhage risk is heightened
Solution Approach 1:
Plasma kallikrein inhibitors serve as protective intermediaries that prevent excessive thrombin generation and control bleeding risk. By blocking the contact activation pathway, they reduce the likelihood of intracranial hemorrhage while preserving the beneficial clot-dissolving effect of fibrinolytic therapy
3Object-affected harmful factors
If plasma kallikrein is inhibited, then thrombin generation is reduced and bleeding risk is minimized, but the complexity of the coagulation system increases
Solution Approach 1:
The patent extracts and targets a specific component (plasma kallikrein) within the complex coagulation system. By focusing inhibition on this single enzyme that activates the contact pathway, the patent simplifies the approach to managing coagulation complexity rather than attempting to control all coagulation factors simultaneously
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 effectively inhibit plasma kallikrein, reducing thrombin generation, promoting clot dissolution, and preventing reocclusion while minimizing bleeding risks, thus improving the efficacy of fibrinolytic therapy.
Implementation Method 1
The compounds and their pharmaceutically acceptable salts are useful as inhibitors of human plasma kallikrein
Data Source
AI summary
Disclosed are compounds of formula Ias described herein, and pharmaceutically acceptable salts thereof. The compounds are inhibitors of plasma kallikrein. Also provided are pharmaceutical compositions comprising at least one compound of the invention, and methods involving use of the compounds and compositions of the invention in the treatment and prevention of diseases and conditions characterized by unwanted plasma kallikrein activity.