Polymer-assisted solution-phase (PASP) parallel synthesis of an alpha-ketothiazole library as tissue factor VIIa inhibitors.
A solution-phase synthesis of an alpha-ketothiazole library of the general form D-Phe-L-AA-L-Arg-alpha-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 alpha-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 alpha-ketothiazoles were found to be potent, reversible-covalent inhibitors of tissue factor VIIa, with some analogues demonstrating selectivity versus thrombin.
South
Michael S
MS
Department of Medicinal and Combinatorial Chemistry, Pharmacia Corporation, 800 North Lindbergh Boulevard, 63167, St. Louis, MO, USA. michael.s.south@pharmacia.com
Dice
Thomas A
TA
Girard
Thomas J
TJ
Lachance
Rhonda M
RM
Stevens
Anna M
AM
Stegeman
Roderick A
RA
Stallings
William C
WC
Kurumbail
Ravi G
RG
Parlow
John J
JJ
D000925:Anticoagulants / Q000138:chemical synthesis* / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D065427:Factor Xa Inhibitors; D006801:Humans; D007202:Indicators and Reagents; D008958:Models, Molecular; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors
D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D007202:Indicators and Reagents; D013844:Thiazoles; C481397:alpha-ketothiazole; D015942:Factor VIIa; D013917:Thrombin