Identification and initial structure-activity relationships of a novel class of nonpeptide inhibitors of blood coagulation factor Xa.
The discovery and some of the basic structure-activity relationships of a series of novel nonpeptide inhibitors of blood coagulation Factor Xa is described. These inhibitors are functionalized beta-alanines, exemplified by 2a. Docking experiments placing 2a in the active site of Factor Xa implied that the most expeditious route to enhancing in vitro potency was to modify the group occupying the S3 site of the enzyme. Increasing the hydrophobic contacts between the inhibitor and the enzyme in this region led to 8, which has served as the prototype for this series. In addition, an enantioselective synthesis of these substituted beta-alanines was also developed.
Klein
S I
SI
Department of Cardiovascular Drug Discovery, Collegeville, Pennsylvania 19426, USA.
Czekaj
M
M
Gardner
C J
CJ
Guertin
K R
KR
Cheney
D L
DL
Spada
A P
AP
Bolton
S A
SA
Brown
K
K
Colussi
D
D
Heran
C L
CL
Morgan
S R
SR
Leadley
R J
RJ
Dunwiddie
C T
CT
Perrone
M H
MH
Chu
V
V
D000818:Animals; D001665:Binding Sites; D002417:Cattle; D015195:Drug Design; D015951:Factor Xa / Q000737:chemistry; D065427:Factor Xa Inhibitors; D006801:Humans; D006860:Hydrogen Bonding; D007202:Indicators and Reagents; D007231:Infant, Newborn; D008958:Models, Molecular; D008968:Molecular Conformation; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors; D014361:Trypsin Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015091:beta-Alanine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
D065427:Factor Xa Inhibitors; D007202:Indicators and Reagents; D014361:Trypsin Inhibitors; D015091:beta-Alanine; D013917:Thrombin; D015951:Factor Xa