Novel bicyclic lactam inhibitors of thrombin: potency and selectivity optimization through P1 residues.
Peptidomimetic inhibitors of thrombin lacking the important Ser195-carbonyl interaction have been prepared. The binding energy lost after the removal of the activated carbonyl was recaptured through a series of modifications of the P1 residues of the bicyclic lactam inhibitors. Selected substituted compounds displayed useful pharmacological profiles both in vitro and in vivo.
Lévesque
S
S
Shire BioChem Inc., 275 Armand-Frappier Blvd., Laval, H7V 4A7, Québec, Canada. slevesque@ca.shire.com
St-Denis
Y
Y
Bachand
B
B
Préville
P
P
Leblond
L
L
Winocour
P D
PD
Edmunds
J J
JJ
Rubin
J R
JR
Siddiqui
M A
MA
D000818:Animals; D000991:Antithrombins / Q000737:chemistry / Q000494:pharmacology*; D001158:Arteries / Q000187:drug effects; D066298:In Vitro Techniques; D007769:Lactams / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D013917:Thrombin / Q000037:antagonists & inhibitors*
D000991:Antithrombins; D007769:Lactams; D013917:Thrombin