TY - JOUR
T1 - Polymer-Assisted Solution-Phase (PASP) parallel synthesis of an α-ketothiazole library as tissue factor VIIa inhibitors
AU - South, Michael S.
AU - Dice, Thomas A.
AU - Girard, Thomas J.
AU - Lachance, Rhonda M.
AU - Stevens, Anna M.
AU - Stegeman, Roderick A.
AU - Stallings, William C.
AU - Kurumbail, Ravi G.
AU - Parlow, John J.
N1 - Funding Information:
The authors thank Dr. Huey Shieh for some of the early crystallographic refinements of the TF/VIIa structure. Diffraction data for the TF/VIIa complex with the ketothiazole inhibitor were collected at beamline 17-ID in the facilities of the Industrial Macromolecular Crystallography Association Collaborative Access Team (IMCA-CAT) at the Advanced Photon Source. IMCA-CAT facilities are supported by the corporate members of the IMCA and through a contract with Illinois Institute of Technology (IIT), executed through the IIT's Center for Synchrotron Radiation Research and Instrumentation. Use of the Advanced Photon Source was supported by the US Department of Energy, Basic Energy Sciences, Office of Science, under Contract No. W-31-109-Eng-38.
PY - 2003/7/21
Y1 - 2003/7/21
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=0037666158&partnerID=8YFLogxK
U2 - 10.1016/S0960-894X(03)00398-6
DO - 10.1016/S0960-894X(03)00398-6
M3 - Article
C2 - 12824035
AN - SCOPUS:0037666158
SN - 0960-894X
VL - 13
SP - 2363
EP - 2367
JO - Bioorganic and Medicinal Chemistry Letters
JF - Bioorganic and Medicinal Chemistry Letters
IS - 14
ER -