Abstract
A solution-phase synthesis of an alpha-ketothiazole library of the general form D-Phe-L-AA-Arg-alpha-ketothiazole is described. The five-step synthesis is accomplished using a combination of polymeric reagents and polymer-assisted solution-phase purification concepts, including reactant-sequestering resins, reagent-sequestering resins, and tagged reagents. The multistep synthesis affords desired alpha-ketothiazole products in excellent purities and yields. A variety of L-amino acid inputs were used to probe the S2 pocket of tissue Factor VIIa enzyme to influence both potency and selectivity. An X-ray crystal structure of compound 10k bound to the TF/VIIa complex was obtained that explains the observed selectivity. The alpha-ketothiazoles were found to be potent, reversible-covalent inhibitors of tissue Factor VIIa, with some analogues demonstrating selectivity over thrombin.
Publication types
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
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Amino Acid Sequence
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Binding Sites
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Combinatorial Chemistry Techniques / methods*
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Crystallography, X-Ray
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Enzyme Inhibitors / chemistry
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Enzyme Inhibitors / metabolism
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Enzyme Inhibitors / pharmacology
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Factor VIIa / antagonists & inhibitors*
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Factor VIIa / genetics
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Factor VIIa / metabolism
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Humans
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Inhibitory Concentration 50
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Ketones / chemistry*
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Models, Molecular
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Polymers / chemistry
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Recombinant Proteins / antagonists & inhibitors
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Recombinant Proteins / genetics
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Recombinant Proteins / metabolism
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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 / metabolism
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Thiazoles / pharmacology*
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Thrombin / antagonists & inhibitors
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Thrombin / metabolism
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Thromboplastin / antagonists & inhibitors*
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Thromboplastin / genetics
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Thromboplastin / metabolism
Substances
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Enzyme Inhibitors
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Ketones
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Polymers
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Recombinant Proteins
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Thiazoles
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Thromboplastin
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Factor VIIa
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Thrombin