Incorporation of neutral C-terminal residues in 3-amidinophenylalanine-derived matriptase inhibitors.
A novel series of matriptase inhibitors based on previously identified tribasic 3-amidinophenylalanine derivatives was prepared. The C-terminal basic group was replaced by neutral residues to reduce the hydrophilicity of the inhibitors. The most potent compound 22 inhibits matriptase with a K(i) value of 0.43 nM, but lacks selectivity towards factor Xa. By combination with neutral N-terminal sulfonyl residues several potent thrombin inhibitors were identified, which had reduced matriptase affinity.
Schweinitz
Andrea
A
The Medicines Company (Leipzig) GmbH, Deutscher Platz 5d, D-04103 Leipzig, Germany.
Dönnecke
Daniel
D
Ludwig
Alexander
A
Steinmetzer
Peter
P
Schulze
Alexander
A
Kotthaus
Joscha
J
Wein
Silvia
S
Clement
Bernd
B
Steinmetzer
Torsten
T
D000284:Administration, Oral; D000578:Amidines / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D015951:Factor Xa / Q000378:metabolism; D065427:Factor Xa Inhibitors; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D012697:Serine Endopeptidases / Q000737:chemistry* / Q000378:metabolism; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology; D013449:Sulfonamides / Q000737:chemistry* / Q000494:pharmacology; D013917:Thrombin / Q000037:antagonists & inhibitors / Q000378:metabolism
D000578:Amidines; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D010649:Phenylalanine; D012697:Serine Endopeptidases; C485595:matriptase; D013917:Thrombin; D015951:Factor Xa