100223-00-5Relevant academic research and scientific papers
Polymer-assisted solution-phase library synthesis and crystal structure of α-ketothiazoles as tissue factor VIIa inhibitors
Parlow, John J.,Dice, Thomas A.,Lachance, Rhonda M.,Girard, Thomas J.,Stevens, Anna M.,Stegeman, Roderick A.,Stallings, William C.,Kurumbail, Ravi G.,South, Michael S.
, p. 4043 - 4049 (2007/10/03)
A solution-phase synthesis of an α-ketothiazole library of the general form D-Phe-L-AA-Arg-α-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 α-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 α-ketothiazoles were found to be potent, reversible-covalent inhibitors of tissue Factor VIIa, with some analogues demonstrating selectivity over thrombin.
