Bicyclic pyridones as potent, efficacious and orally bioavailable thrombin inhibitors.
A new class of conformationally constrained thrombin inhibitors is described. These compounds contain a unique bicyclic pyridone scaffold which serves as a P3P2 dipeptide surrogate. The synthesis and antithrombotic activity of these inhibitors is reported.
Coburn
C A
CA
Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. craig_coburn@merck.com
Rush
D M
DM
Williams
P D
PD
Homnick
C
C
Lyle
E A
EA
Lewis
S D
SD
Lucas
B J
BJ
Di Muzio-Mower
J M
JM
Juliano
M
M
Krueger
J A
JA
Vastag
K
K
Chen
I W
IW
Vacca
J P
JP
D000081:Acetamides / Q000737:chemistry* / Q000494:pharmacology*; D000631:Aminopyridines / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D000925:Anticoagulants / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D001682:Biological Availability; D004151:Dipeptides / Q000737:chemistry; D004285:Dogs; D015195:Drug Design; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D018716:Molecular Mimicry; D011728:Pyridones / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000037:antagonists & inhibitors*; D013927:Thrombosis / Q000188:drug therapy
D000081:Acetamides; D000631:Aminopyridines; D000925:Anticoagulants; D004151:Dipeptides; D011728:Pyridones; D013917:Thrombin