Abstract
Potent serine protease inhibitor 1a featuring a hybrid P3-P4 quaternary lactam dipeptide surrogate was prepared based upon SAR and molecular modeling investigations and in order to further probe the S2/S3 thrombin and FXa subsites. An efficient and concise synthetic route to the key aminolactam intermediate 4 was developed. The design, synthesis, and biological activity of this target and its P3-P4 diastereomer 1b is presented.
MeSH terms
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Chromatography, High Pressure Liquid
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Dipeptides* / chemistry
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Guanidines / chemistry*
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Guanidines / metabolism
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Humans
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In Vitro Techniques
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Lactams* / chemistry
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Magnetic Resonance Spectroscopy
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Models, Chemical
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Models, Molecular
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Molecular Structure
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Piperidines / chemistry*
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Piperidines / metabolism
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Serine Proteinase Inhibitors / chemical synthesis*
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Serine Proteinase Inhibitors / chemistry
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Structure-Activity Relationship
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Thrombin / antagonists & inhibitors*
Substances
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CVS 1578
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CVS 1897
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Dipeptides
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Guanidines
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Lactams
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Piperidines
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Serine Proteinase Inhibitors
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Thrombin