Abstract
Inhibiting the classical pathway of complement activation by attenuating the proteolytic activity of the serine protease C1s is a potential strategy for the therapeutic intervention in disease states such as hereditary angioedema, ischemia-reperfusion injury, and acute transplant rejection. A series of arylsulfonylthiophene-2-carboxamidine inhibitors of C1s were synthesized and evaluated for C1s inhibitory activity. The most potent compound had a Ki of 10nM and >1000-fold selectivity over uPA, tPA, FX(a), thrombin, and plasmin.
MeSH terms
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Amidines / chemical synthesis
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Amidines / pharmacology
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Angioedema / drug therapy
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Arylsulfonates / chemical synthesis*
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Arylsulfonates / pharmacology
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Complement C1s / antagonists & inhibitors*
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Fibrinolysin / pharmacology
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Graft Rejection / drug therapy
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Humans
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Myocardial Ischemia / drug therapy
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Serine Proteinase Inhibitors / chemical synthesis*
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Serine Proteinase Inhibitors / pharmacology
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Structure-Activity Relationship
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Tetradecanoylphorbol Acetate / pharmacology
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Thiophenes / chemical synthesis
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Thiophenes / pharmacology
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Thrombin / pharmacology
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Urokinase-Type Plasminogen Activator / pharmacology
Substances
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Amidines
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Arylsulfonates
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Serine Proteinase Inhibitors
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Thiophenes
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Complement C1s
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Thrombin
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Fibrinolysin
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Urokinase-Type Plasminogen Activator
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Tetradecanoylphorbol Acetate