title: Incorporation of neutral C-terminal residues in 3-amidinophenylalanine-derived matriptase inhibitors.
abstract: 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.
authors.affiliation: The Medicines Company (Leipzig) GmbH, Deutscher Platz 5d, D-04103 Leipzig, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Schweinitz
authors.forename: Daniel
authors.initials: D
authors.lastname: Dönnecke
authors.forename: Alexander
authors.initials: A
authors.lastname: Ludwig
authors.forename: Peter
authors.initials: P
authors.lastname: Steinmetzer
authors.forename: Alexander
authors.initials: A
authors.lastname: Schulze
authors.forename: Joscha
authors.initials: J
authors.lastname: Kotthaus
authors.forename: Silvia
authors.initials: S
authors.lastname: Wein
authors.forename: Bernd
authors.initials: B
authors.lastname: Clement
authors.forename: Torsten
authors.initials: T
authors.lastname: Steinmetzer
mesh_terms: 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
chemical_list: D000578:Amidines; D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors; D013449:Sulfonamides; D010649:Phenylalanine; D012697:Serine Endopeptidases; C485595:matriptase; D013917:Thrombin; D015951:Factor Xa