title: Polymer-assisted solution-phase (PASP) parallel synthesis of an alpha-ketothiazole library as tissue factor VIIa inhibitors.
abstract: 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.
authors.affiliation: Department of Medicinal and Combinatorial Chemistry, Pharmacia Corporation, 800 North Lindbergh Boulevard, 63167, St. Louis, MO, USA. michael.s.south@pharmacia.com
authors.forename: Michael S
authors.initials: MS
authors.lastname: South
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Dice
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Girard
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Lachance
authors.forename: Anna M
authors.initials: AM
authors.lastname: Stevens
authors.forename: Roderick A
authors.initials: RA
authors.lastname: Stegeman
authors.forename: William C
authors.initials: WC
authors.lastname: Stallings
authors.forename: Ravi G
authors.initials: RG
authors.lastname: Kurumbail
authors.forename: John J
authors.initials: JJ
authors.lastname: Parlow
mesh_terms: 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
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D007202:Indicators and Reagents; D013844:Thiazoles; C481397:alpha-ketothiazole; D015942:Factor VIIa; D013917:Thrombin