title: Rational design, synthesis, and biological activity of benzoxazinones as novel factor Xa inhibitors.
abstract: Inappropriate thrombus formation within blood vessels is the leading cause of mortality in the industrialized world. Factor Xa (FXa) is a trypsin-like serine protease that plays a key role in the blood coagulation cascade and represents an attractive target for anticoagulant drug development. From a high-throughput in vitro mass screen of our chemical library, we identified 4-[5-[(2R,6S)-2, 6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-2-phenyl-2H-1, 4-benzoxazin-3(4H)-one (1a) as an inhibitor of FXa with an IC(50) of 27 microM. Through a combination of SAR studies and molecular modeling, we synthesized 3-(4-[5-[(2R,6S)-2, 6-dimethyltetrahydro-1(2H)-pyridinyl]pentyl]-3-oxo-3,4-dihydro-2H- 1,4-benzoxazin-2-yl)-1-benzenecarboximidamide (1n) which was a potent FXa inhibitor with an IC(50) of 3 nM. This compound exhibited high selectivity for FXa over other related serine proteases and was efficacious when dosed intravenously in rabbit and dog antithrombotic models.
authors.affiliation: Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. Danette.Dudley@pfizer.com
authors.forename: D A
authors.initials: DA
authors.lastname: Dudley
authors.forename: A M
authors.initials: AM
authors.lastname: Bunker
authors.forename: L
authors.initials: L
authors.lastname: Chi
authors.forename: W L
authors.initials: WL
authors.lastname: Cody
authors.forename: D R
authors.initials: DR
authors.lastname: Holland
authors.forename: D P
authors.initials: DP
authors.lastname: Ignasiak
authors.forename: N
authors.initials: N
authors.lastname: Janiczek-Dolphin
authors.forename: T B
authors.initials: TB
authors.lastname: McClanahan
authors.forename: T E
authors.initials: TE
authors.lastname: Mertz
authors.forename: L S
authors.initials: LS
authors.lastname: Narasimhan
authors.forename: S T
authors.initials: ST
authors.lastname: Rapundalo
authors.forename: J A
authors.initials: JA
authors.lastname: Trautschold
authors.forename: C A
authors.initials: CA
authors.lastname: Van Huis
authors.forename: J J
authors.initials: JJ
authors.lastname: Edmunds
mesh_terms: D000284:Administration, Oral; D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D048588:Benzoxazines; D001682:Biological Availability; D020650:Combinatorial Chemistry Techniques; D004285:Dogs; D015195:Drug Design; D065427:Factor Xa Inhibitors; D005341:Fibrinolysin / Q000037:antagonists & inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D007275:Injections, Intravenous; D008958:Models, Molecular; D010078:Oxazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011817:Rabbits; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology
chemical_list: C416346:3-(4-(5-(2,6-dimethyltetrahydro-1(2H)-pyridinyl)pentyl)-3-oxo-3,4-dihydro-2H-1,4-benzoxazin-2-yl)-1-benzenecarboximidamide; D000578:Amidines; D048588:Benzoxazines; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D010078:Oxazines; D015842:Serine Proteinase Inhibitors; D014361:Trypsin Inhibitors; D013917:Thrombin; D005341:Fibrinolysin