Abstract
The discovery and SAR of ketopiperazino methylazaindole factor Xa inhibitors are described. Structure-activity data suggesting that this class of inhibitors does not bind in the canonical mode were confirmed by an X-ray crystal structure showing the neutral haloaromatic bound in the S(1) subsite. The most potent azaindole, 33 (RPR209685), is selective against related serine proteases and attains higher levels of exposure upon oral dosing than comparable benzamidines and benzamidine isosteres. Compound 33 was efficacious in the canine AV model of thrombosis.
MeSH terms
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Administration, Oral
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Animals
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Aza Compounds / chemical synthesis*
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Aza Compounds / chemistry
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Aza Compounds / pharmacology
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Biological Availability
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Crystallography, X-Ray
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Dogs
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Factor Xa Inhibitors*
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In Vitro Techniques
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Indoles / chemical synthesis*
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Indoles / chemistry
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Indoles / pharmacology
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Ligands
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Microsomes, Liver / drug effects
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Microsomes, Liver / metabolism
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Piperazines / chemical synthesis*
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Piperazines / chemistry
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Piperazines / pharmacology
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Rats
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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
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Sulfonamides / chemical synthesis*
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Sulfonamides / chemistry
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Sulfonamides / pharmacology
Substances
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Aza Compounds
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Factor Xa Inhibitors
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Indoles
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Ligands
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Piperazines
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RPR 209685
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Serine Proteinase Inhibitors
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Sulfonamides