title: Phenyltriazolinones as potent factor Xa inhibitors.
abstract: 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.
authors.affiliation: Research and Development, Bristol-Myers Squibb, PO Box 5400, Princeton, NJ 08543-5400, USA. mimi.quan@bms.com
authors.forename: Mimi L
authors.initials: ML
authors.lastname: Quan
authors.forename: Donald J P
authors.initials: DJ
authors.lastname: Pinto
authors.forename: Karen A
authors.initials: KA
authors.lastname: Rossi
authors.forename: Steven
authors.initials: S
authors.lastname: Sheriff
authors.forename: Richard S
authors.initials: RS
authors.lastname: Alexander
authors.forename: Eugene
authors.initials: E
authors.lastname: Amparo
authors.forename: Kevin
authors.initials: K
authors.lastname: Kish
authors.forename: Robert M
authors.initials: RM
authors.lastname: Knabb
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.forename: Paul
authors.initials: P
authors.lastname: Morin
authors.forename: Angela
authors.initials: A
authors.lastname: Smallwood
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Woerner
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
mesh_terms: 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
chemical_list: 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