Phenyltriazolinones as potent factor Xa inhibitors.
We have discovered that phenyltriazolinone is a novel and potent P1 moiety for coagulation factor Xa. X-ray structures of the inhibitors with a phenyltriazolinone in the P1 position revealed that the side chain of Asp189 has reoriented resulting in a novel S1 binding pocket which is larger in size to accommodate the phenyltriazolinone P1 substrate.
Quan
Mimi L
ML
Research and Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, USA. mimi.quan@bms.com
Pinto
Donald J P
DJ
Rossi
Karen A
KA
Sheriff
Steven
S
Alexander
Richard S
RS
Amparo
Eugene
E
Kish
Kevin
K
Knabb
Robert M
RM
Luettgen
Joseph M
JM
Morin
Paul
P
Smallwood
Angela
A
Woerner
Francis J
FJ
Wexler
Ruth R
RR
D000925:Anticoagulants / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018360:Crystallography, X-Ray; D015195:Drug Design; D065427:Factor Xa Inhibitors; D006801:Humans; D007555:Isoxazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D008958:Models, Molecular; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011728:Pyridones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013450:Sulfones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
C421624:1-(3-(aminomethyl)phenyl)-N-(3-fluoro-2'-(methylsulfonyl)(1,1'-biphenyl)-4-yl)-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide; D000925:Anticoagulants; D065427:Factor Xa Inhibitors; D007555:Isoxazoles; D011720:Pyrazoles; D011728:Pyridones; D013450:Sulfones; C500057:razaxaban; C522181:apixaban