603137-72-0Relevant academic research and scientific papers
Polymer-Assisted Solution-Phase (PASP) parallel synthesis of an α-ketothiazole library as tissue factor VIIa inhibitors
South, Michael S.,Dice, Thomas A.,Girard, Thomas J.,Lachance, Rhonda M.,Stevens, Anna M.,Stegeman, Roderick A.,Stallings, William C.,Kurumbail, Ravi G.,Parlow, John J.
, p. 2363 - 2367 (2007/10/03)
A solution-phase synthesis of an α-ketothiazole library of the general form D-Phe-L-AA-L-Arg-α-ketothiazole is described. The five-step synthesis is accomplished using a combination of polymeric reagents and polymer-assisted solution-phase purification protocols, including reactant-sequestering resins, reagent-sequestering resins, and tagged reagents. The multi-step synthesis affords the desired α-ketothiazole products in excellent purities and yields. A variety of L-amino acid inputs were used to probe the S2 pocket of the tissue factor (TF) VIIa enzyme to influence both potency and selectivity. An X-ray crystal structure of compound 10e 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 versus thrombin.
