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J Med Chem. 2003 Feb 13;46(4):461-73.

Metabolism-directed optimization of 3-aminopyrazinone acetamide thrombin inhibitors. Development of an orally bioavailable series containing P1 and P3 pyridines.

Author information

1
Departments of Medicinal Chemistry, Biological Chemistry, Drug Metabolism, Molecular Systems, Structural Biology, and Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. christopher_burgey@merck.com

Abstract

Recent efforts in the field of thrombin inhibitor research have focused on the identification of compounds with good oral bioavailability and pharmacokinetics. In this manuscript we describe a metabolism-based approach to the optimization of the 3-(2-phenethylamino)-6-methylpyrazinone acetamide template (e.g., 1) which resulted in the modification of each of the three principal components (i.e., P1, P2, P3) comprising this series. As a result of these studies, several potent thrombin inhibitors (e.g., 20, 24, 25) were identified which exhibit high levels of oral bioavailability and long plasma half-lives.

PMID:
12570369
DOI:
10.1021/jm020311f
[Indexed for MEDLINE]

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