title: Novel, potent and selective chimeric FXa inhibitors featuring hydrophobic P1-ketoamide moieties.
abstract: Judicious combination of P-region sequences of highly potent anticoagulant proteins including NAP5, NAP6, Ecotin, and Antistasin with SAR from small molecule FXa inhibitors led to a series of chimeric inhibitors of formula 1a-j. We report herein the design, synthesis, and biological activity of this novel family of FXa inhibitors that express both high in vitro potency and superb selectivity against related serine proteases.
authors.affiliation: Department of Medicinal Chemistry, Corvas International, Inc., San Diego, CA 92121, USA. ed_semple@corvas.com
authors.forename: J E
authors.initials: JE
authors.lastname: Semple
authors.forename: O E
authors.initials: OE
authors.lastname: Levy
authors.forename: N K
authors.initials: NK
authors.lastname: Minami
authors.forename: T D
authors.initials: TD
authors.lastname: Owens
authors.forename: D V
authors.initials: DV
authors.lastname: Siev
mesh_terms: D000933:Antifibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001426:Bacterial Proteins / Q000737:chemistry; D015195:Drug Design; D029968:Escherichia coli Proteins; D065427:Factor Xa Inhibitors; D015801:Helminth Proteins / Q000737:chemistry; D006801:Humans; D007447:Invertebrate Hormones / Q000737:chemistry; D015394:Molecular Structure; D033903:Periplasmic Proteins; D011993:Recombinant Fusion Proteins / Q000037:antagonists & inhibitors; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000933:Antifibrinolytic Agents; D001426:Bacterial Proteins; C039076:Eco protein, E coli; D029968:Escherichia coli Proteins; D065427:Factor Xa Inhibitors; D015801:Helminth Proteins; D007447:Invertebrate Hormones; D033903:Periplasmic Proteins; D011993:Recombinant Fusion Proteins; D015842:Serine Proteinase Inhibitors; C108605:anti-coagulant protein 5, Ancylostoma caninum; C053155:antistasin