title: Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with monoaryl P4 motifs.
abstract: Structure and property based drug design was exploited in the synthesis of sulfonamidopyrrolidin-2-one-based factor Xa inhibitors, incorporating neutral and basic monoaryl P4 groups, ultimately producing potent inhibitors with effective levels of anticoagulant activity and extended oral pharmacokinetic profiles. However, time dependant inhibition of Cytochrome P450 3A4 was a particular issue with this series.
authors.affiliation: GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom.
authors.forename: Savvas
authors.initials: S
authors.lastname: Kleanthous
authors.forename: Alan D
authors.initials: AD
authors.lastname: Borthwick
authors.forename: David
authors.initials: D
authors.lastname: Brown
authors.forename: Cynthia L
authors.initials: CL
authors.lastname: Burns-Kurtis
authors.forename: Matthew
authors.initials: M
authors.lastname: Campbell
authors.forename: Laiq
authors.initials: L
authors.lastname: Chaudry
authors.forename: Chuen
authors.initials: C
authors.lastname: Chan
authors.forename: Marie-Olive
authors.initials: MO
authors.lastname: Clarte
authors.forename: Máire A
authors.initials: MA
authors.lastname: Convery
authors.forename: John D
authors.initials: JD
authors.lastname: Harling
authors.forename: Eric
authors.initials: E
authors.lastname: Hortense
authors.forename: Wendy R
authors.initials: WR
authors.lastname: Irving
authors.forename: Stephanie
authors.initials: S
authors.lastname: Irvine
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Pateman
authors.forename: Angela N
authors.initials: AN
authors.lastname: Patikis
authors.forename: Ivan L
authors.initials: IL
authors.lastname: Pinto
authors.forename: Derek R
authors.initials: DR
authors.lastname: Pollard
authors.forename: Theresa J
authors.initials: TJ
authors.lastname: Roethka
authors.forename: Stefan
authors.initials: S
authors.lastname: Senger
authors.forename: Gita P
authors.initials: GP
authors.lastname: Shah
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Stelman
authors.forename: John R
authors.initials: JR
authors.lastname: Toomey
authors.forename: Nigel S
authors.initials: NS
authors.lastname: Watson
authors.forename: Robert I
authors.initials: RI
authors.lastname: West
authors.forename: Caroline
authors.initials: C
authors.lastname: Whittaker
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Young
mesh_terms: D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D003198:Computer Simulation; D018360:Crystallography, X-Ray; D015195:Drug Design; D005170:Factor X / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011760:Pyrrolidinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D013329:Structure-Activity Relationship
chemical_list: D000925:Anticoagulants; D011760:Pyrrolidinones; D005170:Factor X