title: Design and synthesis of orally active pyrrolidin-2-one-based factor Xa inhibitors.
abstract: A series of novel, non-basic 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group, was designed and synthesised. Within this series, the N-2-(morpholin-4-yl)-2-oxoethyl derivative 24 was shown to be a potent, selective fXa inhibitor with good anticoagulant activity. Moreover, 24 possessed highly encouraging rat and dog pharmacokinetic profiles with excellent oral bioavailabilities in both species.
authors.affiliation: GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Nigel.S.Watson@gsk.com
authors.forename: Nigel S
authors.initials: NS
authors.lastname: Watson
authors.forename: David
authors.initials: D
authors.lastname: Brown
authors.forename: Matthew
authors.initials: M
authors.lastname: Campbell
authors.forename: Chuen
authors.initials: C
authors.lastname: Chan
authors.forename: Laiq
authors.initials: L
authors.lastname: Chaudry
authors.forename: Máire A
authors.initials: MA
authors.lastname: Convery
authors.forename: Rebecca
authors.initials: R
authors.lastname: Fenwick
authors.forename: J Nicole
authors.initials: JN
authors.lastname: Hamblin
authors.forename: Claudine
authors.initials: C
authors.lastname: Haslam
authors.forename: Henry A
authors.initials: HA
authors.lastname: Kelly
authors.forename: N Paul
authors.initials: NP
authors.lastname: King
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Kurtis
authors.forename: Andrew R
authors.initials: AR
authors.lastname: Leach
authors.forename: Gary R
authors.initials: GR
authors.lastname: Manchee
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Mason
authors.forename: Charlotte
authors.initials: C
authors.lastname: Mitchell
authors.forename: Champa
authors.initials: C
authors.lastname: Patel
authors.forename: Vipulkumar K
authors.initials: VK
authors.lastname: Patel
authors.forename: Stefan
authors.initials: S
authors.lastname: Senger
authors.forename: Gita P
authors.initials: GP
authors.lastname: Shah
authors.forename: Helen E
authors.initials: HE
authors.lastname: Weston
authors.forename: Caroline
authors.initials: C
authors.lastname: Whitworth
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Young
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000990:Antithrombin III / Q000138:chemical synthesis / Q000494:pharmacology*; D001682:Biological Availability; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D008297:Male; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D013917:Thrombin / Q000187:drug effects*
chemical_list: D005343:Fibrinolytic Agents; D011760:Pyrrolidinones; D000990:Antithrombin III; D013917:Thrombin