title: Polymer-assisted solution-phase library synthesis and crystal structure of alpha-ketothiazoles as tissue factor VIIa inhibitors.
abstract: A solution-phase synthesis of an alpha-ketothiazole library of the general form D-Phe-L-AA-Arg-alpha-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 alpha-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 alpha-ketothiazoles were found to be potent, reversible-covalent inhibitors of tissue Factor VIIa, with some analogues demonstrating selectivity over thrombin.
authors.affiliation: Department of Medicinal and Combinatorial Chemistry, Pharmacia Corporation, 800 North Lindbergh Boulevard, St. Louis, Missouri 63167, USA. john.j.parlow@pfizer.com
authors.forename: John J
authors.initials: JJ
authors.lastname: Parlow
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Dice
authors.forename: Rhonda M
authors.initials: RM
authors.lastname: Lachance
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Girard
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: Michael S
authors.initials: MS
authors.lastname: South
mesh_terms: D000595:Amino Acid Sequence; D001665:Binding Sites; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D015942:Factor VIIa / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D007659:Ketones / Q000737:chemistry*; D008958:Models, Molecular; D011108:Polymers / Q000737:chemistry; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism; D013925:Thromboplastin / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D007659:Ketones; D011108:Polymers; D011994:Recombinant Proteins; D013844:Thiazoles; D013925:Thromboplastin; D015942:Factor VIIa; D013917:Thrombin