Design, synthesis, and activity of 2,6-diphenoxypyridine-derived factor Xa inhibitors.
A novel series of 2,6-diphenoxypyridines has been designed to inhibit factor Xa, a serine protease strategically located in the coagulation cascade. The evolution from the photochemically unstable bisamidine (Z,Z)-BABCH to potent bisamidine compounds with a pyridine heterocycle as the core scaffold has been achieved. The most potent compound in the series, 6h, has a Ki for human factor Xa of 12 nM. The selectivity of 6h against bovine trypsin and human thrombin was greater than 90- and 1000-fold, respectively. Two proposed modes of binding of 6h to factor Xa are made based on the crystal structures of 6h by itself and of 6h bound to bovine trypsin.
Phillips
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Discovery Research, Berlex Biosciences, 15049 San Pablo Avenue, P.O. Box 4099, Richmond, California 94804-0099, USA.
Davey
D D
DD
Eagen
K A
KA
Koovakkat
S K
SK
Liang
A
A
Ng
H P
HP
Pinkerton
M
M
Trinh
L
L
Whitlow
M
M
Beatty
A M
AM
Morrissey
M M
MM
D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry; D000818:Animals; D002417:Cattle; D018360:Crystallography, X-Ray; D015195:Drug Design; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D008968:Molecular Conformation; D011725:Pyridines / Q000138:chemical synthesis* / Q000737:chemistry; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000737:chemistry
C119211:3,3'-(3,5-difluoro-4-methyl-2,6-pyridinediylbis(oxy))bis(benzenecarbox(imide)amide); D000578:Amidines; D065427:Factor Xa Inhibitors; D005343:Fibrinolytic Agents; D011725:Pyridines; D014361:Trypsin Inhibitors; D013917:Thrombin