title: Discovery of novel P1 groups for coagulation factor VIIa inhibition using fragment-based screening.
abstract: A multidisciplinary, fragment-based screening approach involving protein ensemble docking and biochemical and NMR assays is described. This approach led to the discovery of several structurally diverse, neutral surrogates for cationic factor VIIa P1 groups, which are generally associated with poor pharmacokinetic (PK) properties. Among the novel factor VIIa inhibitory fragments identified were aryl halides, lactams, and heterocycles. Crystallographic structures for several bound fragments were obtained, leading to the successful design of a potent factor VIIa inhibitor with a neutral lactam P1 and improved permeability.
authors.affiliation: †Bristol-Myers Squibb Co., Research and Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08543, United States.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Cheney
authors.affiliation: †Bristol-Myers Squibb Co., Research and Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08543, United States.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Bozarth
authors.forename: William J
authors.initials: WJ
authors.lastname: Metzler
authors.forename: Paul E
authors.initials: PE
authors.lastname: Morin
authors.forename: Luciano
authors.initials: L
authors.lastname: Mueller
authors.forename: John A
authors.initials: JA
authors.lastname: Newitt
authors.affiliation: †Bristol-Myers Squibb Co., Research and Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08543, United States.
authors.forename: Alexandra H
authors.initials: AH
authors.lastname: Nirschl
authors.affiliation: †Bristol-Myers Squibb Co., Research and Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08543, United States.
authors.forename: Alan R
authors.initials: AR
authors.lastname: Rendina
authors.forename: James K
authors.initials: JK
authors.lastname: Tamura
authors.affiliation: †Bristol-Myers Squibb Co., Research and Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08543, United States.
authors.forename: Anzhi
authors.initials: A
authors.lastname: Wei
authors.affiliation: †Bristol-Myers Squibb Co., Research and Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08543, United States.
authors.forename: Xiao
authors.initials: X
authors.lastname: Wen
authors.affiliation: †Bristol-Myers Squibb Co., Research and Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08543, United States.
authors.forename: Nicholas R
authors.initials: NR
authors.lastname: Wurtz
authors.affiliation: †Bristol-Myers Squibb Co., Research and Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08543, United States.
authors.forename: Dietmar A
authors.initials: DA
authors.lastname: Seiffert
authors.affiliation: †Bristol-Myers Squibb Co., Research and Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08543, United States.
authors.forename: Ruth R
authors.initials: RR
authors.lastname: Wexler
authors.affiliation: †Bristol-Myers Squibb Co., Research and Development, 311 Pennington-Rocky Hill Road, Pennington, New Jersey 08543, United States.
authors.forename: E Scott
authors.initials: ES
authors.lastname: Priestley
mesh_terms: D001777:Blood Coagulation / Q000187:drug effects; D018360:Crystallography, X-Ray; D015195:Drug Design; D015942:Factor VIIa / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006219:Halogens / Q000737:chemistry / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D007769:Lactams / Q000378:metabolism / Q000494:pharmacology; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D015842:Serine Proteinase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D006219:Halogens; D006571:Heterocyclic Compounds; D007769:Lactams; D015842:Serine Proteinase Inhibitors; D015942:Factor VIIa