title: D-phenylglycinol-derived non-covalent factor Xa inhibitors: effect of non-peptidic S4 linkage elements on affinity and anticoagulant activity.
abstract: Analogs to a series of D-phenylglycinamide-derived factor Xa inhibitors were discovered. It was found that the S4 amide linkage can be replaced with an ether linkage to reduce the peptide character of the molecules and that this substitution leads to an increase in binding affinity that is not predicted based on modeling. Inhibitors which incorporate ether, amino, or alkyl S4 linkage motifs exhibit similar levels of binding affinity and also demonstrate potent in vitro functional activity, however, binding affinity in this series is strongly dependent on the nature of the S1 binding element.
authors: Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
authors: Valentine J
authors: VJ
authors: Klimkowski
authors: Brian M
authors: BM
authors: Watson
authors: Michael R
authors: MR
authors: Wiley
authors: John
authors: J
authors: Liebeschuetz
authors: Jeffry B
authors: JB
authors: Franciskovich
authors: Jothirajah
authors: J
authors: Marimuthu
authors: Jolie A
authors: JA
authors: Bastian
authors: Daniel J
authors: DJ
authors: Sall
authors: Jeffrey K
authors: JK
authors: Smallwood
authors: Nikolay Y
authors: NY
authors: Chirgadze
authors: Gerald F
authors: GF
authors: Smith
authors: Ronald S
authors: RS
authors: Foster
authors: Trelia
authors: T
authors: Craft
authors: Philip
authors: P
authors: Sipes
authors: Marcia
authors: M
authors: Chastain
authors: Scott M
authors: SM
authors: Sheehan
mesh_terms: D000925:Anticoagulants / Q000737:chemistry / Q000494:pharmacology*; D018360:Crystallography, X-Ray; D004983:Ethanolamines; D065427:Factor Xa Inhibitors; D005998:Glycine / Q000031:analogs & derivatives* / Q000737:chemistry; D008958:Models, Molecular; D010455:Peptides / Q000737:chemistry; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D000925:Anticoagulants; D004983:Ethanolamines; D065427:Factor Xa Inhibitors; D010455:Peptides; D015842:Serine Proteinase Inhibitors; C005332:N-phenylethanolamine; D005998:Glycine