The discovery of glycine and related amino acid-based factor Xa inhibitors.
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.
Kohrt
Jeffrey T
JT
Pfizer Global Research and Development, Michigan Labs, Ann Arbor, 48105, USA. jeffrey.kohrt@pfizer.com
Filipski
Kevin J
KJ
Cody
Wayne L
WL
Bigge
Christopher F
CF
La
Frances
F
Welch
Kathleen
K
Dahring
Tawny
T
Bryant
John W
JW
Leonard
Daniele
D
Bolton
Gary
G
Narasimhan
Lakshmi
L
Zhang
Erli
E
Peterson
J Thomas
JT
Haarer
Staci
S
Sahasrabudhe
Vaishali
V
Janiczek
Nancy
N
Desiraju
Shrilakshmi
S
Hena
Mostofa
M
Fiakpui
Charles
C
Saraswat
Neerja
N
Sharma
Raman
R
Sun
Shaoyi
S
Maiti
Samarendra N
SN
Leadley
Robert
R
Edmunds
Jeremy J
JJ
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*
D065427:Factor Xa Inhibitors; D015842:Serine Proteinase Inhibitors; D015951:Factor Xa; D005998:Glycine