title: Structure-based drug design of pyrrolidine-1, 2-dicarboxamides as a novel series of orally bioavailable factor Xa inhibitors.
abstract: 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.
authors.forename: Chad A
authors.initials: CA
authors.lastname: Van Huis
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Bigge
authors.forename: Agustin
authors.initials: A
authors.lastname: Casimiro-Garcia
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Cody
authors.forename: Danette A
authors.initials: DA
authors.lastname: Dudley
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Filipski
authors.forename: Ronald J
authors.initials: RJ
authors.lastname: Heemstra
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Kohrt
authors.forename: Lakshmi S
authors.initials: LS
authors.lastname: Narasimhan
authors.forename: Robert P
authors.initials: RP
authors.lastname: Schaum
authors.forename: Erli
authors.initials: E
authors.lastname: Zhang
authors.forename: John W
authors.initials: JW
authors.lastname: Bryant
authors.forename: Staci
authors.initials: S
authors.lastname: Haarer
authors.forename: Nancy
authors.initials: N
authors.lastname: Janiczek
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Leadley
authors.forename: Thomas
authors.initials: T
authors.lastname: McClanahan
authors.forename: J
authors.initials: J
authors.lastname: Thomas Peterson
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Welch
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Edmunds
mesh_terms: 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
chemical_list: D000990:Antithrombin III; D011761:Pyrrolidonecarboxylic Acid