title: Highly potent and selective substrate analogue factor Xa inhibitors containing D-homophenylalanine analogues as P3 residue: part 2.
abstract: A series of highly potent substrate-analogue factor Xa inhibitors containing D-homophenylalanine analogues as the P3 residue has been identified by systematic optimization of a previously described inhibitor structure. An initial lead, benzylsulfonyl-D-hPhe-Gly-4-amidinobenzylamide (3), inhibits fXa with an inhibition constant of 6.0 nM. Most modifications of the P2 amino acid and P4 benzylsulfonyl group did not improve the affinity and selectivity of the compounds as fXa inhibitors. In contrast, further variation at the P3 position led to inhibitors with significantly enhanced potency and selectivity. Inhibitor 27, benzylsulfonyl-D-homo-2-pyridylalanyl(N-oxide)-Gly-4-amidinobenzylamide, inhibits fXa with a K(i) value of 0.32 nM. The inhibitor has strong anticoagulant activity in plasma and doubles the activated partial thromboplastin time and prothrombin time at concentrations of 280 nM and 170 nM, respectively. Compound 27 inhibits the prothrombinase complex with an IC(50) value of 5 nM and is approximately 50 times more potent than the reference inhibitor DX-9065a in this assay.
authors.affiliation: Curacyte Discovery GmbH, Winzerlaer Str. 2, 07745 Jena, Germany.
authors.forename: Anne
authors.initials: A
authors.lastname: Stürzebecher
authors.forename: Daniel
authors.initials: D
authors.lastname: Dönnecke
authors.forename: Andrea
authors.initials: A
authors.lastname: Schweinitz
authors.forename: Oliver
authors.initials: O
authors.lastname: Schuster
authors.forename: Peter
authors.initials: P
authors.lastname: Steinmetzer
authors.forename: Uta
authors.initials: U
authors.lastname: Stürzebecher
authors.forename: Joscha
authors.initials: J
authors.lastname: Kotthaus
authors.forename: Bernd
authors.initials: B
authors.lastname: Clement
authors.forename: Jörg
authors.initials: J
authors.lastname: Stürzebecher
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
mesh_terms: D000613:Aminobutyrates / Q000737:chemistry*; D000818:Animals; D000925:Anticoagulants / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D065427:Factor Xa Inhibitors; D006801:Humans; D007700:Kinetics; D010084:Oxidation-Reduction; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000097:blood / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013379:Substrate Specificity
chemical_list: D000613:Aminobutyrates; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors; C014328:2-amino-4-phenylbutyric acid