Structure-based drug design of pyrrolidine-1, 2-dicarboxamides as a novel series of orally bioavailable factor Xa inhibitors.
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, IC(50) = 18 nM). Optimization of the initial hit resulted in an orally bioavailable, subnanomolar inhibitor of factor Xa (13, IC(50) = 0.38 nM), which was shown to be efficacious in a canine electrolytic model of thrombosis with minimal bleeding.
Van Huis
Chad A
CA
Bigge
Christopher F
CF
Casimiro-Garcia
Agustin
A
Cody
Wayne L
WL
Dudley
Danette A
DA
Filipski
Kevin J
KJ
Heemstra
Ronald J
RJ
Kohrt
Jeffrey T
JT
Narasimhan
Lakshmi S
LS
Schaum
Robert P
RP
Zhang
Erli
E
Bryant
John W
JW
Haarer
Staci
S
Janiczek
Nancy
N
Leadley
Robert J
RJ
McClanahan
Thomas
T
Thomas Peterson
J
J
Welch
Kathleen M
KM
Edmunds
Jeremy J
JJ
D000284:Administration, Oral; D000818:Animals; D000990:Antithrombin III / Q000737:chemistry* / Q000494:pharmacology; D002626:Chemistry, Pharmaceutical / Q000379:methods*; D003460:Crystallization; D004285:Dogs; D015195:Drug Design; D006801:Humans; D020128:Inhibitory Concentration 50; D008956:Models, Chemical; D008958:Models, Molecular; D011485:Protein Binding; D011761:Pyrrolidonecarboxylic Acid / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013997:Time Factors
D000990:Antithrombin III; D011761:Pyrrolidonecarboxylic Acid