Abstract
In this manuscript we demonstrate that a modification principally directed toward the improvement of the aqueous solubility (i.e., introduction a P3 pyridine N-oxide) of the previous lead compound afforded a new series of potent orally bioavailable P1 N-benzylamide thrombin inhibitors. An expedited investigation of the P1 SAR with respect to oral bioavailability, plasma half-life, and human liver microsome stability revealed 5 as the best candidate for advanced evaluation.
MeSH terms
-
Acetamides / chemical synthesis*
-
Acetamides / pharmacology*
-
Animals
-
Biological Availability
-
Chemical Phenomena
-
Chemistry, Physical
-
Crystallography, X-Ray
-
Dogs
-
Half-Life
-
Humans
-
In Vitro Techniques
-
Injections, Intravenous
-
Macaca mulatta
-
Microsomes, Liver / metabolism
-
Models, Molecular
-
Oxides / chemistry
-
Pyrazines / chemical synthesis*
-
Pyrazines / pharmacology*
-
Pyridines / chemistry*
-
Rats
-
Solubility
-
Structure-Activity Relationship
-
Thrombin / antagonists & inhibitors*
-
Thrombosis / chemically induced
-
Thrombosis / drug therapy
Substances
-
3-amino-6-chloropyrazinone acetamide
-
Acetamides
-
Oxides
-
Pyrazines
-
Pyridines
-
Thrombin