title: Selective and dual action orally active inhibitors of thrombin and factor Xa.
abstract: The synthetic entry to new classes of dual fXa/thrombin and selective thrombin inhibitors with significant oral bioavailability is described. This was achieved through minor modifications to the sulfonamide group in our potent and selective fXa inhibitor (E)-2-(5-chlorothien-2-yl)-N-{(3S)-1-[(1S)-1-methyl-2-(morpholin-4-yl)-2-oxoethyl]-2-oxopyrrolidin-3-yl}ethenesulfonamide and these observed activity changes have been rationalised using structural studies.
authors.affiliation: GlaxoSmithKline, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, UK. Rob.J.Young@gsk.com
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Young
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: Julia A
authors.initials: JA
authors.lastname: Hubbard
authors.forename: Henry A
authors.initials: HA
authors.lastname: Kelly
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Pateman
authors.forename: Angela
authors.initials: A
authors.lastname: Patikis
authors.forename: Stefan
authors.initials: S
authors.lastname: Senger
authors.forename: Gita P
authors.initials: GP
authors.lastname: Shah
authors.forename: John R
authors.initials: JR
authors.lastname: Toomey
authors.forename: Nigel S
authors.initials: NS
authors.lastname: Watson
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
mesh_terms: D000818:Animals; D004285:Dogs; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology*; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: C521365:2-(5-chlorothien-2-yl)-N-((3S)-1-((1S)-1-methyl-2-(morpholin-4-yl)-2-oxoethyl)-2-oxopyrrolidin-3-yl)ethenesulfonamide; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D009025:Morpholines; D013449:Sulfonamides; D013917:Thrombin