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Title
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Polymer-assisted solution-phase library synthesis and crystal structure of alpha-ketothiazoles as tissue factor VIIa inhibitors.
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Authors
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J.J.Parlow,
T.A.Dice,
R.M.Lachance,
T.J.Girard,
A.M.Stevens,
R.A.Stegeman,
W.C.Stallings,
R.G.Kurumbail,
M.S.South.
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Ref.
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J Med Chem, 2003,
46,
4043-4049.
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PubMed id
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Abstract
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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.
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