D-phenylglycinol-derived non-covalent factor Xa inhibitors: effect of non-peptidic S4 linkage elements on affinity and anticoagulant activity.
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.
Klimkowski
Valentine J
VJ
Lilly Research Laboratories, A Division of Eli Lilly and Company, Indianapolis, IN 46285, USA.
Watson
Brian M
BM
Wiley
Michael R
MR
Liebeschuetz
John
J
Franciskovich
Jeffry B
JB
Marimuthu
Jothirajah
J
Bastian
Jolie A
JA
Sall
Daniel J
DJ
Smallwood
Jeffrey K
JK
Chirgadze
Nikolay Y
NY
Smith
Gerald F
GF
Foster
Ronald S
RS
Craft
Trelia
T
Sipes
Philip
P
Chastain
Marcia
M
Sheehan
Scott M
SM
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*
D000925:Anticoagulants; D004983:Ethanolamines; D065427:Factor Xa Inhibitors; D010455:Peptides; D015842:Serine Proteinase Inhibitors; C005332:N-phenylethanolamine; D005998:Glycine