Identification and SAR for a selective, nonpeptidyl thrombin inhibitor.
A novel, nonpeptidyl thrombin inhibitor, L-636,619 (1), was identified via topological similarity searching over the Merck Corporate Sample Database. X-ray crystallographic studies determined the geometry for ligand binding to the enzyme. Chemical modification of the P1 and P3 segments of the ligand resulted in enhanced potency and improvement in the chemical stability of the lead. Analog 9 proved to be the most interesting lead from this structurally novel series.
Naylor-Olsen
A M
AM
Department of Molecular Design and Diversity, Merck Research Laboratories, West Point, PA 19486, USA.
Ponticello
G S
GS
Lewis
S D
SD
Mulichak
A M
AM
Chen
Z
Z
Habecker
C N
CN
Phillips
B T
BT
Sanders
W M
WM
Tucker
T J
TJ
Shafer
J A
JA
Vacca
J P
JP
D000991:Antithrombins / Q000737:chemistry* / Q000494:pharmacology; D001665:Binding Sites; D003461:Crystallography; D008958:Models, Molecular; D013329:Structure-Activity Relationship
D000991:Antithrombins