Rational design, synthesis, and biological activity of benzoxazinones as novel factor Xa inhibitors.
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.
Dudley
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DA
Pfizer Global Research and Development, 2800 Plymouth Road, Ann Arbor, Michigan 48105, USA. Danette.Dudley@pfizer.com
Bunker
A M
AM
Chi
L
L
Cody
W L
WL
Holland
D R
DR
Ignasiak
D P
DP
Janiczek-Dolphin
N
N
McClanahan
T B
TB
Mertz
T E
TE
Narasimhan
L S
LS
Rapundalo
S T
ST
Trautschold
J A
JA
Van Huis
C A
CA
Edmunds
J J
JJ
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
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