title: The discovery of glycine and related amino acid-based factor Xa inhibitors.
abstract: Herein, we report on the identification of three potent glycine and related amino acid-based series of FXa inhibitors containing a neutral P1 chlorophenyl pharmacophore. A X-ray crystal structure has shown that constrained glycine derivatives with optimized N-substitution can greatly increase hydrophobic interactions in the FXa active site. Also, the substitution of a pyridone ring for a phenylsulfone ring in the P4 sidechain resulted in an inhibitor with enhanced oral bioavailability.
authors.affiliation: Pfizer Global Research and Development, Michigan Labs, Ann Arbor, 48105, USA. jeffrey.kohrt@pfizer.com
authors.forename: Jeffrey T
authors.initials: JT
authors.lastname: Kohrt
authors.forename: Kevin J
authors.initials: KJ
authors.lastname: Filipski
authors.forename: Wayne L
authors.initials: WL
authors.lastname: Cody
authors.forename: Christopher F
authors.initials: CF
authors.lastname: Bigge
authors.forename: Frances
authors.initials: F
authors.lastname: La
authors.forename: Kathleen
authors.initials: K
authors.lastname: Welch
authors.forename: Tawny
authors.initials: T
authors.lastname: Dahring
authors.forename: John W
authors.initials: JW
authors.lastname: Bryant
authors.forename: Daniele
authors.initials: D
authors.lastname: Leonard
authors.forename: Gary
authors.initials: G
authors.lastname: Bolton
authors.forename: Lakshmi
authors.initials: L
authors.lastname: Narasimhan
authors.forename: Erli
authors.initials: E
authors.lastname: Zhang
authors.forename: J Thomas
authors.initials: JT
authors.lastname: Peterson
authors.forename: Staci
authors.initials: S
authors.lastname: Haarer
authors.forename: Vaishali
authors.initials: V
authors.lastname: Sahasrabudhe
authors.forename: Nancy
authors.initials: N
authors.lastname: Janiczek
authors.forename: Shrilakshmi
authors.initials: S
authors.lastname: Desiraju
authors.forename: Mostofa
authors.initials: M
authors.lastname: Hena
authors.forename: Charles
authors.initials: C
authors.lastname: Fiakpui
authors.forename: Neerja
authors.initials: N
authors.lastname: Saraswat
authors.forename: Raman
authors.initials: R
authors.lastname: Sharma
authors.forename: Shaoyi
authors.initials: S
authors.lastname: Sun
authors.forename: Samarendra N
authors.initials: SN
authors.lastname: Maiti
authors.forename: Robert
authors.initials: R
authors.lastname: Leadley
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Edmunds
mesh_terms: D018360:Crystallography, X-Ray; D015951:Factor Xa / Q000737:chemistry*; D065427:Factor Xa Inhibitors; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry*; D006801:Humans; D015394:Molecular Structure; D011487:Protein Conformation; D015842:Serine Proteinase Inhibitors / Q000737:chemistry*
chemical_list: D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors; D015951:Factor Xa; D005998:Glycine