Abstract
Inhibitors of human mast cell tryptase (EC 3.4.21.59) have therapeutic potential for treating allergic or inflammatory disorders. We have investigated transition-state mimetics possessing a heterocycle-activated ketone group and identified in particular benzothiazole ketone (2S)-6 (RWJ-56423) as a potent, reversible, low-molecular-weight tryptase inhibitor with a K(i) value of 10 nM. A single-crystal X-ray analysis of the sulfate salt of (2S)-6 confirmed the stereochemistry. Analogues 12 and 15-17 are also potent tryptase inhibitors. Although RWJ-56423 potently inhibits trypsin (K(i) = 8.1 nM), it is selective vs other serine proteases, such as kallikrein, plasmin, and thrombin. We obtained an X-ray structure of (2S)-6 complexed with bovine trypsin (1.9-A resolution), which depicts inter alia a hemiketal involving Ser-189, and hydrogen bonds with His-57 and Gln-192. Aerosol administration of 6 (2R,2S; RWJ-58643) to allergic sheep effectively antagonized antigen-induced asthmatic responses, with 70-75% blockade of the early response and complete ablation of the late response and airway hyperresponsiveness.
MeSH terms
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Aerosols
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Animals
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Anti-Asthmatic Agents / chemical synthesis*
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Anti-Asthmatic Agents / chemistry
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Anti-Asthmatic Agents / pharmacology
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Asthma / drug therapy
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Asthma / immunology
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Asthma / physiopathology
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Benzothiazoles
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Cattle
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Crystallography, X-Ray
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Dipeptides / chemistry*
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Humans
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Ketones / chemical synthesis*
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Ketones / chemistry
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Ketones / pharmacology
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Kinetics
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Mast Cells / enzymology
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Models, Molecular
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Protein Binding
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Pyrrolidines / chemical synthesis*
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Pyrrolidines / chemistry
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Pyrrolidines / pharmacology
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Serine Endopeptidases / metabolism*
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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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Sheep
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Stereoisomerism
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Structure-Activity Relationship
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Thiazoles / chemical synthesis*
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Thiazoles / chemistry
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Thiazoles / pharmacology
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Trypsin / chemistry
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Tryptases
Substances
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1-acetyl-N-(4-((aminoiminomethyl)amino)-1-(2-benzothiazolylcarbonyl)butyl)-4-hydroxy-2-pyrrolidinecarboxamide
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Aerosols
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Anti-Asthmatic Agents
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Benzothiazoles
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Dipeptides
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Ketones
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Pyrrolidines
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Serine Proteinase Inhibitors
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Thiazoles
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Serine Endopeptidases
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Trypsin
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Tryptases