Abstract
The design, synthesis and SAR of a novel class of valerolactam-based arylsulfonamides as potent and selective FXa inhibitors is reported. The arylsulfonamide-valerolactam scaffold was derived based on the proposed bioisosterism to the arylcyanoguanidine-caprolactam core in known FXa inhibitors. The SAR study led to compound 46 as the most potent FXa inhibitor in this series, with an IC(50) of 7 nM and EC(2×PT) of 1.7 μM. The X-ray structure of compound 40 bound to FXa shows that the sulfonamide-valerolactam scaffold anchors the aryl group in the S1 and the novel acylcytisine pharmacophore in the S4 pockets.
Copyright © 2011 Elsevier Ltd. All rights reserved.
MeSH terms
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Anticoagulants / chemical synthesis
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Anticoagulants / chemistry*
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Anticoagulants / pharmacology
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Binding Sites
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Crystallography, X-Ray
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Enzyme Activation / drug effects
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Factor Xa / metabolism
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Factor Xa Inhibitors*
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Humans
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Lactams / chemistry
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Molecular Conformation
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Piperidones / chemical synthesis
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Piperidones / chemistry*
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Piperidones / pharmacology
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Protein Structure, Tertiary
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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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Anticoagulants
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Factor Xa Inhibitors
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Lactams
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Piperidones
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Serine Proteinase Inhibitors
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valerolactam
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Factor Xa