Novel, potent and selective chimeric FXa inhibitors featuring hydrophobic P1-ketoamide moieties.
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.
Semple
J E
JE
Department of Medicinal Chemistry, Corvas International, Inc., San Diego, CA 92121, USA. ed_semple@corvas.com
Levy
O E
OE
Minami
N K
NK
Owens
T D
TD
Siev
D V
DV
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
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