Potent and selective bicyclic lactam inhibitors of thrombin: Part 2: P1 modifications.
The synthesis and antithrombotic activity of a series of nonpeptide bicyclic thrombin inhibitors is described. We have explored the SAR with modifications to the P1 site. The introduction of arginine mimetics at the P1 site led to potent and selective thrombin inhibitors.
Plummer
J S
JS
Parke-Davis Pharmaceutical Research, Division of Warner-Lambert Company, Ann Arbor, MI 48105, USA.
Berryman
K A
KA
Cai
C
C
Cody
W L
WL
DiMaio
J
J
Doherty
A M
AM
Edmunds
J J
JJ
He
J X
JX
Holland
D R
DR
Levesque
S
S
Kent
D R
DR
Narasimhan
L S
LS
Rubin
J R
JR
Rapundalo
S T
ST
Siddiqui
M A
MA
Susser
A J
AJ
St-Denis
Y
Y
Winocour
P D
PD
D000818:Animals; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D007769:Lactams / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D015842:Serine Proteinase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*
D005343:Fibrinolytic Agents; D007769:Lactams; D015842:Serine Proteinase Inhibitors; D013917:Thrombin