title: Design and synthesis of potent, selective phenylimidazole-based FVIIa inhibitors.
abstract: Heterocyclic amide isosteres were incorporated into a phenylglycine-based tissue factor/factor VIIa (TF-FVIIa) inhibitor chemotype, providing potent inhibitors. An X-ray co-crystal structure of phenylimidazole 19 suggested that an imidazole nitrogen atom effectively mimics an amide carbonyl, while the phenyl ring forms key hydrophobic interactions with the S1' pocket. Exploration of phenylimidazole substitution led to the discovery of potent, selective and efficacious inhibitors of TF-FVIIa.
authors.affiliation: Bristol-Myers Squibb R&D, 311 Pennington-Rocky Hill Rd, Pennington, NJ 08534, United States. Electronic address: peter.glunz@bms.com.
authors.forename: Peter W
authors.initials: PW
authors.lastname: Glunz
authors.affiliation: Bristol-Myers Squibb R&D, 311 Pennington-Rocky Hill Rd, Pennington, NJ 08534, United States.
authors.forename: Xuhong
authors.initials: X
authors.lastname: Cheng
authors.affiliation: Bristol-Myers Squibb R&D, 311 Pennington-Rocky Hill Rd, Pennington, NJ 08534, United States.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Cheney
authors.affiliation: Bristol-Myers Squibb R&D, 311 Pennington-Rocky Hill Rd, Pennington, NJ 08534, United States.
authors.forename: Carolyn A
authors.initials: CA
authors.lastname: Weigelt
authors.affiliation: Bristol-Myers Squibb R&D, 311 Pennington-Rocky Hill Rd, Pennington, NJ 08534, United States.
authors.forename: Anzhi
authors.initials: A
authors.lastname: Wei
authors.affiliation: Bristol-Myers Squibb R&D, 311 Pennington-Rocky Hill Rd, Pennington, NJ 08534, United States.
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Luettgen
authors.affiliation: Bristol-Myers Squibb R&D, 311 Pennington-Rocky Hill Rd, Pennington, NJ 08534, United States.
authors.forename: Pancras C
authors.initials: PC
authors.lastname: Wong
authors.affiliation: Bristol-Myers Squibb R&D, 311 Pennington-Rocky Hill Rd, Pennington, NJ 08534, United States.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.affiliation: Bristol-Myers Squibb R&D, 311 Pennington-Rocky Hill Rd, Pennington, NJ 08534, United States.
authors.forename: E Scott
authors.initials: ES
authors.lastname: Priestley
mesh_terms: D018360:Crystallography, X-Ray; D015195:Drug Design; D015942:Factor VIIa / Q000037:antagonists & inhibitors*; D007093:Imidazoles / Q000737:chemistry*; D015394:Molecular Structure; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D007093:Imidazoles; D015842:Serine Proteinase Inhibitors; D015942:Factor VIIa
keywords: Amide isosteres; Factor VIIa; Serine protease inhibitors; TF–FVIIa inhibitor; Tissue factor