Urethanyl-3-amidinophenylalanine derivatives as inhibitors of factor Xa. X-ray crystal structure of a trypsin/inhibitor complex and modeling studies.
Hydrophobic urethanyl derivatives of 3-amidinophenylalanine methyl ester were found to be relatively potent and selective factor Xa inhibitors. These compounds consist of the arginine-mimetic 3-benzamidino group as P1 residue and of hydrophobic residues as potential interaction partners for the S3/S4 aryl binding site of the enzyme. Attempts to possibly identify their binding mode to factor Xa via the X-ray crystal structure of a trypsin/inhibitor complex and analogy modeling on the crystal structure of factor Xa failed. However, synthesis of enantiomerically pure (R)- and (S)-derivatives, combined with modeling experiments, led to an hypothetical non-substrate like binding mode, which was fully confirmed by the remarkably enhanced inhibitory potency of derivatives in which the methyl ester was replaced by arylamides for interactions with the S3/S4 enzyme binding subsites. With adamantyloxycarbonyl-(R)-3-amidinophenylalanine-phenethylamide+ ++ a nanomolar inhibiton was obtained, thus indicating this new class of factor Xa inhibitors as a highly promising lead structure.
Sperl
S
S
Max-Planck-Institut für Biochemie, Martinsried, Germany.
Bergner
A
A
Stürzebecher
J
J
Magdolen
V
V
Bode
W
W
Moroder
L
L
D000818:Animals; D001665:Binding Sites; D002417:Cattle; D018360:Crystallography, X-Ray; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000737:chemistry; D006860:Hydrogen Bonding; D008956:Models, Chemical; D008958:Models, Molecular; D008968:Molecular Conformation; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology; D011485:Protein Binding; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism; D013917:Thrombin / Q000737:chemistry / Q000378:metabolism; D014357:Trypsin / Q000737:chemistry / Q000378:metabolism; D014361:Trypsin Inhibitors / Q000737:chemistry / Q000378:metabolism; D014520:Urethane / Q000031:analogs & derivatives / Q000737:chemistry* / Q000494:pharmacology
D004791:Enzyme Inhibitors; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D014361:Trypsin Inhibitors; D014520:Urethane; D010649:Phenylalanine; D012697:Serine Endopeptidases; D014357:Trypsin; D013917:Thrombin