title: Structure- and property-based design of factor Xa inhibitors: pyrrolidin-2-ones with acyclic alanyl amides as P4 motifs.
abstract: Structure-based drug design was exploited in the synthesis of 3-(6-chloronaphth-2-ylsulfonyl)aminopyrrolidin-2-one-based factor Xa (fXa) inhibitors, incorporating an alanylamide P4 group with acyclic tertiary amide termini. Optimized hydrophobic contacts of one amide substituent in P4 were complemented by hydrophobicity-modulating features in the second, producing potent fXa inhibitors including examples with excellent anticoagulant properties.
authors.affiliation: GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Rob.J.Young@gsk.com <Rob.J.Young@gsk.com>
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Young
authors.forename: Matthew
authors.initials: M
authors.lastname: Campbell
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: Chuen
authors.initials: C
authors.lastname: Chan
authors.forename: Máire A
authors.initials: MA
authors.lastname: Convery
authors.forename: Miriam C
authors.initials: MC
authors.lastname: Crowe
authors.forename: Satish
authors.initials: S
authors.lastname: Dayal
authors.forename: Hawa
authors.initials: H
authors.lastname: Diallo
authors.forename: Henry A
authors.initials: HA
authors.lastname: Kelly
authors.forename: N Paul
authors.initials: NP
authors.lastname: King
authors.forename: Savvas
authors.initials: S
authors.lastname: Kleanthous
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Mason
authors.forename: Jackie E
authors.initials: JE
authors.lastname: Mordaunt
authors.forename: Champa
authors.initials: C
authors.lastname: Patel
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Pateman
authors.forename: Stefan
authors.initials: S
authors.lastname: Senger
authors.forename: Gita P
authors.initials: GP
authors.lastname: Shah
authors.forename: Paul W
authors.initials: PW
authors.lastname: Smith
authors.forename: Nigel S
authors.initials: NS
authors.lastname: Watson
authors.forename: Helen E
authors.initials: HE
authors.lastname: Weston
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
mesh_terms: D000409:Alanine / Q000737:chemistry*; D000577:Amides / Q000737:chemistry*; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D000990:Antithrombin III / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D018360:Crystallography, X-Ray; D015195:Drug Design; D015951:Factor Xa / Q000737:chemistry / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011758:Pyrroles / Q000737:chemistry*; D013329:Structure-Activity Relationship
chemical_list: D000577:Amides; D000925:Anticoagulants; D011758:Pyrroles; D000990:Antithrombin III; D015951:Factor Xa; D000409:Alanine