Macrocyclic Factor XIa Inhibitors for Selective Anticoagulation
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Solution Overview
Problem
Current anticoagulants for thromboembolic disorders, such as warfarin, have limitations including a narrow therapeutic index, slow onset of effect, dietary and drug interactions, and the need for monitoring, necessitating the development of safer and more effective oral anticoagulants.
Innovation Solution
Development of novel macrocyclic compounds and their analogues that act as selective inhibitors of Factor XIa and/or plasma kallikrein to inhibit thrombin generation, thereby preventing thromboembolic disorders.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If warfarin is used as an anticoagulant, then thromboembolic disorders are treated, but the therapeutic index is narrow and monitoring is required
Solution Approach 1:
The patent changes the molecular parameters of anticoagulants by developing macrocyclic compounds with specific structural features (Formula I with defined ring systems, linkers, and substituents) that selectively inhibit Factor XIa. This parameter change in the drug molecule structure enables improved therapeutic index and eliminates monitoring requirements compared to warfarin
2Reliability
If warfarin is used for anticoagulation, then thromboembolic prevention is achieved, but onset of therapeutic effect is slow
Solution Approach 1:
The patent substitutes the mechanism of action from warfarin's indirect inhibition (requiring synthesis of new clotting factors) to direct Factor XIa inhibition by macrocyclic compounds. This mechanistic substitution achieves rapid onset of therapeutic effect while maintaining anticoagulation effectiveness
3Reliability
If warfarin is administered, then anticoagulation is achieved, but dietary and drug interactions occur
Solution Approach 1:
The patent applies local quality by designing macrocyclic compounds with specific localized structural features (Formula I with particular ring A, ring B, ring C configurations and substituents) that provide selective binding to Factor XIa. This localized structural optimization confers selectivity that minimizes interactions with other physiological systems, reducing dietary and drug interactions
4Reliability
If Factor XIa inhibition is achieved with macrocyclic compounds, then thrombin generation is inhibited, but selective inhibition must be maintained
Solution Approach 1:
The patent uses macrocyclic compounds as intermediary substances that specifically mediate between the therapeutic goal (thrombin generation inhibition) and the target enzyme (Factor XIa). The macrocyclic structure acts as a selective intermediary that binds Factor XIa with high affinity and specificity, achieving thrombin generation inhibition while maintaining selectivity and avoiding off-target effects
Data Source
AI summary
The present invention provides compounds of Formula (I):or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt thereof, wherein all the variables are as defined herein. These compounds are selective Factor XIa inhibitors or dual inhibitors of fXIa and plasma kallikrein. This invention also relates to pharmaceutical compositions comprising these compounds and methods of treating thromboembolic and/or inflammatory disorders using the same.