Structure-based design of amidinophenylurea-derivatives for factor VIIa inhibition.
The amidinophenylurea scaffold was earlier shown to provide an excellent template for the synthesis of novel and potent inhibitors of the blood coagulation factor VIIa. In this contribution we describe the structure-based design of potent ligands guided by X-ray crystallography, molecular modeling and docking studies. The design and synthetic efforts were directed towards novel modifications to explore the protease binding region close to the S4 subsite.
Klingler
Otmar
O
Aventis Pharma Deutschland GmbH, Building G878, D-65926 Frankfurt, Germany. otmar.klinger@aventis.com
Matter
Hans
H
Schudok
Manfred
M
Donghi
Monica
M
Czech
Joerg
J
Lorenz
Martin
M
Nestler
Hans Peter
HP
Szillat
Hauke
H
Schreuder
Herman
H
D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D015942:Factor VIIa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D015394:Molecular Structure; D010447:Peptide Hydrolases / Q000378:metabolism; D010671:Phenylurea Compounds / Q000138:chemical synthesis* / Q000494:pharmacology
D005343:Fibrinolytic Agents; D010671:Phenylurea Compounds; D010447:Peptide Hydrolases; D015942:Factor VIIa