title: Structure-based design and synthesis of pyrazinones containing novel P1 'side pocket' moieties as inhibitors of TF/VIIa.
abstract: We describe the structure-based design, synthesis, and enzymatic activity of a series of substituted pyrazinones as inhibitors of the TF/VIIa complex. These inhibitors contain substituents meta to the P(1) amidine designed to explore additional interactions with the VIIa residues in the so-called 'S(1) side pocket'. A crystal structure of the designed inhibitors demonstrates the ability of the P(1) side pocket moiety to engage Lys192 and main chain of Gly216 via hydrogen bond interactions, thus, providing additional possibility for chemical modification to improve selectivity and/or physical properties of inhibitors.
authors.affiliation: Department of Medicinal and Combinatorial Chemistry, Pfizer Corp., 800 N. Lindbergh Blvd., St. Louis, MO 63167, USA. barbara.a.schweitzer@pfizer.com
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Schweitzer
authors.forename: William L
authors.initials: WL
authors.lastname: Neumann
authors.forename: Hayat K
authors.initials: HK
authors.lastname: Rahman
authors.forename: Carrie L
authors.initials: CL
authors.lastname: Kusturin
authors.forename: Kirby R
authors.initials: KR
authors.lastname: Sample
authors.forename: Gennadiy I
authors.initials: GI
authors.lastname: Poda
authors.forename: Ravi G
authors.initials: RG
authors.lastname: Kurumbail
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: Michael S
authors.initials: MS
authors.lastname: South
mesh_terms: D001550:Benzamidines / Q000737:chemistry*; D001665:Binding Sites; D015195:Drug Design; D015942:Factor VIIa / Q000037:antagonists & inhibitors* / Q000737:chemistry; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D011485:Protein Binding; D011719:Pyrazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D001550:Benzamidines; D005343:Fibrinolytic Agents; D011719:Pyrazines; D015842:Serine Proteinase Inhibitors; D015942:Factor VIIa; C032157:benzamidine