Dual Factor XIa Inhibitor Compounds for Targeted Anticoagulation
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Solution Overview
Problem
Existing treatments for thrombosis and related conditions, such as thromboembolic disorders, are inadequate in addressing the role of Factor XIa and plasma kallikrein in abnormal blood coagulation, leading to significant mortality and disability.
Innovation Solution
Development of compounds that act as selective or dual inhibitors of Factor XIa and plasma kallikrein, which can be administered to inhibit blood coagulation and treat conditions like thrombosis, embolisms, and fibrotic changes, including formulations for various administration routes and combinations with other therapeutic agents.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing treatments for thrombosis are used, then current standard of care is maintained, but they are inadequate in addressing the role of Factor XIa and plasma kallikrein in abnormal blood coagulation
Solution Approach 1:
The patent segments the coagulation inhibition function into two distinct pathways: Factor XIa inhibition and plasma kallikrein inhibition. This is achieved through dual-specificity compounds that can selectively target either or both pathways, allowing for more precise and adaptable treatment of thrombosis compared to existing single-pathway therapies.
Solution Approach 2:
The patent develops compounds with multi-functional capability to inhibit both Factor XIa and plasma kallikrein. This universal approach allows a single therapeutic agent to address multiple coagulation pathways simultaneously, improving the versatility and effectiveness of thrombosis treatment while reducing the need for multiple separate medications.
2Reliability
If selective or dual inhibitors of Factor XIa and plasma kallikrein are developed, then treatment effectiveness is improved, but drug development complexity increases
Solution Approach 1:
The patent employs composite molecular structures that integrate multiple functional domains within single compounds. These compounds contain structural elements that enable simultaneous or selective binding to both Factor XIa and plasma kallikrein, achieving multi-pathway inhibition through carefully designed composite molecular architectures rather than requiring separate drugs.
Solution Approach 2:
The patent utilizes parameter changes in molecular structure, particularly through isosteric replacements and conformational adjustments, to optimize the dual-inhibition capability of the compounds. By modifying structural parameters such as ring configurations, substituent positions, and stereochemistry, the compounds achieve optimal binding affinity and selectivity for both targets while maintaining developability.
3Reliability
If compounds inhibit both Factor XIa and plasma kallikrein, then synergistic effects are achieved, but selectivity control becomes more difficult
Solution Approach 1:
The patent designs compounds with dynamic conformational flexibility that allows them to adapt their structure for optimal binding to either Factor XIa or plasma kallikrein. The molecular structures contain flexible linkers and rotatable bonds that enable the compounds to adopt different conformations depending on which target they are binding to, facilitating selective dual-inhibition or preferential inhibition of one pathway over the other.
Solution Approach 2:
The patent incorporates local quality variations within the molecular structure, with specific regions optimized for binding to Factor XIa and other regions optimized for plasma kallikrein binding. This spatial differentiation of binding properties within the same molecule allows for controlled selectivity, enabling the compound to preferentially inhibit one pathway while maintaining the capability to inhibit the other when needed.
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 blood coagulation, reducing the risk of thrombosis and associated conditions, offering improved pharmacokinetic profiles and synergistic effects when combined with other anticoagulants.
Implementation Method 1
compounds that act as selective or dual inhibitors of Factor XIa and plasma kallikrein, which can be administered to inhibit blood coagulation
Data Source
AI summary
The present invention provides a compound of Formula I and pharmaceutical compositions comprising one or more compounds of Formula I compounds, and methods for using the compounds for treating or preventing thromboses, embolisms, hypercoagulability or fibrotic changes. The compounds are selective Factor XIa inhibitors or dual inhibitors of Factor XIa and plasma kallikrein.