Macrocyclic FXIa Inhibitors with Alkyl P2' Moieties
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Solution Overview
Problem
Current treatments for thromboembolic disorders and diabetic retinopathy associated with diabetic macular edema lack effective, orally available inhibitors for factor XIa and plasma kallikrein that do not induce anaphylaxis, and existing compounds have limitations due to polar and ionizable functionalities affecting gut permeability.
Innovation Solution
Development of novel macrocyclic compounds and their analogues as selective inhibitors of serine protease enzymes, specifically factor XIa and plasma kallikrein, which are designed to be orally available and minimize anaphylactic reactions, with specific structural features enhancing their efficacy and bioavailability.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If existing factor XIa and plasma kallikrein inhibitors are used, then therapeutic effect is achieved, but oral bioavailability is reduced due to polar and ionizable functionalities
Solution Approach 1:
The patent modifies the chemical structure of factor XIa and plasma kallikrein inhibitors by removing or reducing polar and ionizable functional groups (such as carboxylic acids and amines) that hinder oral absorption. This parameter change in molecular properties enables the compounds to cross the gut barrier while retaining their inhibitory activity against the target enzymes, thereby resolving the contradiction between therapeutic efficacy and oral bioavailability.
2Reliability
If large protein plasma kallikrein inhibitors are used, then plasma kallikrein inhibition is effective, but anaphylactic reactions are induced
Solution Approach 1:
The patent replaces large protein plasma kallikrein inhibitors with small molecule compounds that provide the same therapeutic effect without inducing anaphylaxis. These small molecules act as temporary, non-immunogenic alternatives that achieve plasma kallikrein inhibition through reversible binding, eliminating the harmful immune reactions associated with protein-based therapies.
3Reliability
If warfarin is used for anticoagulation, then thromboembolic disorder treatment is effective, but narrow therapeutic index and numerous interactions limit usage
Solution Approach 1:
The patent extracts and targets a specific upstream component (factor XIa or plasma kallikrein) of the coagulation cascade rather than using warfarin's mechanism of inhibiting vitamin K-dependent factors. This selective inhibition approach provides a more favorable safety profile with fewer drug-diet interactions and a wider therapeutic index, while maintaining effective anticoagulation and treating thromboembolic disorders.
Data Source
AI summary
The present invention provides compounds of Formula (I): or stereoisomers, tautomers, or pharmaceutically acceptable salts 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.