Metabolism-Directed Optimization of 3-Aminopyrazinone Acetamide Thrombin Inhibitors. Development of an Orally Bioavailable Series Containing P1 and P3 Pyridines
Christopher S. Burgey(United States Military Academy), Kyle A. Robinson(United States Military Academy), Terry A. Lyle(United States Military Academy), Philip E.J. Sanderson(United States Military Academy), Sidney D. Lewis(United States Military Academy), Bobby J. Lucas(United States Military Academy), Julie A. Krueger(United States Military Academy), Rominder Singh(United States Military Academy), Cynthia Miller‐Stein(United States Military Academy), Rebecca B. White(United States Military Academy), Bradley K. Wong(United States Military Academy), Elizabeth A. Lyle(United States Military Academy), Peter Williams(United States Military Academy), Craig A. Coburn(United States Military Academy), Bruce D. Dorsey(United States Military Academy), James C. Barrow(United States Military Academy), Maria T. Stranieri(United States Military Academy), Marie A. Holahan(United States Military Academy), Gary R. Sitko(United States Military Academy), Jacquelynn J. Cook(United States Military Academy), Daniel R. McMasters(United States Military Academy), Colleen M. McDonough(United States Military Academy), William M. Sanders(United States Military Academy), Audrey A. Wallace(United States Military Academy), Franklin C. Clayton(United States Military Academy), Dennis L. Bohn(United States Military Academy), Yvonne Leonard(United States Military Academy), Theodore J. Detwiler(United States Military Academy), Joseph J. Lynch(United States Military Academy), Youwei Yan(United States Military Academy), Zhongguo Chen(United States Military Academy), Lawrence Kuo(United States Military Academy), Stephen J. Gardell(United States Military Academy), Jules A. Shafer(United States Military Academy), Joseph P. Vacca(United States Military Academy)
Cited by 121Open Access
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.
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