title: Structure and property based design of factor Xa inhibitors: pyrrolidin-2-ones with aminoindane and phenylpyrrolidine P4 motifs.
abstract: The rational design, syntheses and evaluation of potent sulfonamidopyrrolidin-2-one-based factor Xa inhibitors incorporating aminoindane and phenylpyrrolidine P4 motifs are described. These series delivered highly potent anticoagulant compounds with excellent oral pharmacokinetic profiles; however, significant time dependant P450 inhibition was an issue for the aminoindane series, but this was not observed with the phenylpyrrolidine motif, which produced candidate quality molecules with potential for once-daily oral dosing in humans.
authors.affiliation: GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, United Kingdom. Rob.J.Young@gsk.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Young
authors.forename: Carl
authors.initials: C
authors.lastname: Adams
authors.forename: Mike
authors.initials: M
authors.lastname: Blows
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: Laiq
authors.initials: L
authors.lastname: Chaudry
authors.forename: Máire A
authors.initials: MA
authors.lastname: Convery
authors.forename: David E
authors.initials: DE
authors.lastname: Davies
authors.forename: Anne M
authors.initials: AM
authors.lastname: Exall
authors.forename: Graham
authors.initials: G
authors.lastname: Foster
authors.forename: John D
authors.initials: JD
authors.lastname: Harling
authors.forename: Eric
authors.initials: E
authors.lastname: Hortense
authors.forename: Stephanie
authors.initials: S
authors.lastname: Irvine
authors.forename: Wendy R
authors.initials: WR
authors.lastname: Irving
authors.forename: Steve
authors.initials: S
authors.lastname: Jackson
authors.forename: Savvas
authors.initials: S
authors.lastname: Kleanthous
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Pateman
authors.forename: Angela N
authors.initials: AN
authors.lastname: Patikis
authors.forename: Theresa J
authors.initials: TJ
authors.lastname: Roethka
authors.forename: Stefan
authors.initials: S
authors.lastname: Senger
authors.forename: Gary J
authors.initials: GJ
authors.lastname: Stelman
authors.forename: John R
authors.initials: JR
authors.lastname: Toomey
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: Nigel S
authors.initials: NS
authors.lastname: Watson
mesh_terms: D015195:Drug Design; D065427:Factor Xa Inhibitors; D008958:Models, Molecular; D011759:Pyrrolidines / Q000737:chemistry* / Q000494:pharmacology*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship
chemical_list: D065427:Factor Xa Inhibitors; D011759:Pyrrolidines; D015842:Serine Proteinase Inhibitors