Metabolism-Directed Optimization of 3-Aminopyrazinone Acetamide Thrombin Inhibitors. Development of an Orally Bioavailable Series Containing P1 and P3 Pyridines

• Published in: Journal of medicinal chemistry Vol. 46; no. 4; pp. 461 - 473
• Main Authors: Burgey, Christopher S, Robinson, Kyle A, Lyle, Terry A, Sanderson, Philip E. J, Lewis, S. Dale, Lucas, Bobby J, Krueger, Julie A, Singh, Rominder, Miller-Stein, Cynthia, White, Rebecca B, Wong, Bradley, Lyle, Elizabeth A, Williams, Peter D, Coburn, Craig A, Dorsey, Bruce D, Barrow, James C, Stranieri, Maria T, Holahan, Marie A, Sitko, Gary R, Cook, Jacquelynn J, McMasters, Daniel R, McDonough, Colleen M, Sanders, William M, Wallace, Audrey A, Clayton, Franklin C, Bohn, Dennis, Leonard, Yvonne M, Detwiler, Theodore J, Lynch, Joseph J, Yan, Youwei, Chen, Zhongguo, Kuo, Lawrence, Gardell, Stephen J, Shafer, Jules A, Vacca, Joseph P
• Format: Journal Article
• Language: English
• Published: Washington, DC American Chemical Society 13-02-2003
• Subjects: Acetamides - chemical synthesis; Acetamides - pharmacokinetics; Acetamides - pharmacology; Administration, Oral; Animals; Anticoagulants - chemical synthesis; Anticoagulants - pharmacokinetics; Anticoagulants - pharmacology; Biological and medical sciences; Biological Availability; Blood. Blood coagulation. Reticuloendothelial system; Crystallography, X-Ray; Dogs; Macaca mulatta; Medical sciences; Models, Molecular; Pharmacology. Drug treatments; Protease Inhibitors - chemical synthesis; Protease Inhibitors - chemistry; Protease Inhibitors - pharmacology; Pyrazines - chemical synthesis; Pyrazines - pharmacokinetics; Pyrazines - pharmacology; Pyridines - chemical synthesis; Pyridines - pharmacokinetics; Pyridines - pharmacology; Rats; Structure-Activity Relationship; Thrombin - antagonists & inhibitors; Nitrile; Rat; Nitrogen heterocycle; Active site; Lactam; Monkey; Thrombin; Anticoagulant; Modeling; Pyridine derivatives; Structure activity relation; Chlorine Organic compounds; Molecular model; Primates; Chemical synthesis; Dog; Fissipedia; Carnivora; Serine endopeptidases; Enzyme; Rodentia; Oral administration; Enzyme inhibitor; Pyrazine derivatives; Bioavailability; In vitro; Peptidases; In vivo; Vertebrata; Mammalia; Animal; Hydrolases; Carboxamide; Fluorine Organic compounds; Pharmacokinetics
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm020311f

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.