title: Factor Xa inhibitors: S1 binding interactions of a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides.
abstract: Factor Xa inhibitory activities for a series of N-{(3S)-1-[(1S)-1-methyl-2-morpholin-4-yl-2-oxoethyl]-2-oxopyrrolidin-3-yl}sulfonamides with different P1 groups are described. These data provide insight into binding interactions within the S1 primary specificity pocket; rationales are presented for the derived SAR on the basis of electronic interactions through crystal structures of fXa-ligand complexes and molecular modeling studies. A good correlation between in vitro anticoagulant activities with lipophilicity and the extent of human serum albumin binding is observed within this series of potent fXa inhibitors. Pharmacokinetic profiles in rat and dog, together with selectivity over other trypsin-like serine proteases, identified 1f as a candidate for further evaluation.
authors.affiliation: CVU UK Medicinal Chemistry Department, GlaxoSmithKline Research and Development, Medicines Research Centre, Gunnels Wood Road, Stevenage, Hertfordshire SG1 2NY, United Kingdom. chuen.8chan@gsk.com
authors.forename: Chuen
authors.initials: C
authors.lastname: Chan
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: Chun-wa
authors.initials: CW
authors.lastname: Chung
authors.forename: Máire A
authors.initials: MA
authors.lastname: Convery
authors.forename: J Nicole
authors.initials: JN
authors.lastname: Hamblin
authors.forename: Lisa
authors.initials: L
authors.lastname: Johnstone
authors.forename: Henry A
authors.initials: HA
authors.lastname: Kelly
authors.forename: Savvas
authors.initials: S
authors.lastname: Kleanthous
authors.forename: Angela
authors.initials: A
authors.lastname: Patikis
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: John R
authors.initials: JR
authors.lastname: Toomey
authors.forename: Nigel S
authors.initials: NS
authors.lastname: Watson
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
authors.forename: Ping
authors.initials: P
authors.lastname: Zhou
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D004285:Dogs; D015951:Factor Xa / Q000737:chemistry*; D065427:Factor Xa Inhibitors; D005260:Female; D006801:Humans; D008024:Ligands; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D009025:Morpholines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011517:Prothrombin Time; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012709:Serum Albumin / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D008024:Ligands; D009025:Morpholines; D011759:Pyrrolidines; D012709:Serum Albumin; D013449:Sulfonamides; D015951:Factor Xa