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Highly Potent and Selective Substrate Analogue Factor Xa Inhibitors Containing D ‐Homophenylalanine Analogues as P3 Residue: Part 2
Author(s) -
Stürzebecher Anne,
Dönnecke Daniel,
Schweinitz Andrea,
Schuster Oliver,
Steinmetzer Peter,
Stürzebecher Uta,
Kotthaus Joscha,
Clement Bernd,
Stürzebecher Jörg,
Steinmetzer Torsten
Publication year - 2007
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.200700031
Subject(s) - chemistry , prothrombinase , selectivity , stereochemistry , residue (chemistry) , thrombin , partial thromboplastin time , potency , substrate (aquarium) , biochemistry , in vitro , platelet , catalysis , oceanography , immunology , biology , geology
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 n M . 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 n M . The inhibitor has strong anticoagulant activity in plasma and doubles the activated partial thromboplastin time and prothrombin time at concentrations of 280 n M and 170 n M , respectively. Compound 27 inhibits the prothrombinase complex with an IC 50 value of 5 n M and is approximately 50 times more potent than the reference inhibitor DX‐9065a in this assay.