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Van Huis, Chad A.; Bigge, Christopher F.; Casimiro-Garcia, Agustin; Cody, Wayne L.; Dudley, Danette A.; Filipski, Kevin J.; Heemstra, Ronald J.; Kohrt, Jeffrey T.; Narasimhan, Lakshmi S.; Schaum, Robert P.; Zhang, Erli; Bryant, John W.; Haarer, Staci; Janiczek, Nancy; Leadley Jr, Robert J.; McClanahan, Thomas; Thomas Peterson, J.; Welch, Kathleen M.; Edmunds, Jeremy J.
Chemical biology & drug design, 06/2007, Letnik: 69, Številka: 6Journal Article
A novel series of pyrrolidine‐1,2‐dicarboxamides was discovered as factor Xa inhibitors using structure‐based drug design. This series consisted of a neutral 4‐chlorophenylurea P1, a biphenylsulfonamide P4 and a d‐proline scaffold (1, IC50 = 18 nm). Optimization of the initial hit resulted in an orally bioavailable, subnanomolar inhibitor of factor Xa (13, IC50 = 0.38 nm), which was shown to be efficacious in a canine electrolytic model of thrombosis with minimal bleeding.
