Abstract
A series of macrocyclic factor XIa (FXIa) inhibitors was designed based on an analysis of the crystal structures of the acyclic phenylimidazole compounds. Further optimization using structure-based design led to inhibitors with pM affinity for FXIa, excellent selectivity against a panel of relevant serine proteases, and good potency in the activated partial thromboplastin time (aPTT) clotting assay.
Keywords:
Activated partial thromboplastin time; FXIa; Factor XIa inhibitors; Thrombosis; aPTT.
Copyright © 2017 Elsevier Ltd. All rights reserved.
MeSH terms
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Dose-Response Relationship, Drug
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Factor XIa / antagonists & inhibitors*
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Factor XIa / metabolism
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Humans
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Imidazoles / chemical synthesis
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Imidazoles / chemistry
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Imidazoles / pharmacology*
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Macrocyclic Compounds / chemical synthesis
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Macrocyclic Compounds / chemistry
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Macrocyclic Compounds / pharmacology*
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Molecular Structure
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Serine Proteinase Inhibitors / chemical synthesis
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Serine Proteinase Inhibitors / chemistry
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Serine Proteinase Inhibitors / pharmacology*
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Structure-Activity Relationship
Substances
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Imidazoles
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Macrocyclic Compounds
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Serine Proteinase Inhibitors
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imidazole
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Factor XIa