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

Burgey CS, Robinson KA, Lyle TA, Sanderson PE, Lewis SD, Lucas BJ, Krueger JA, Singh R, Miller-Stein C, White RB, Wong B, Lyle EA, Williams PD, Coburn CA, Dorsey BD, Barrow JC, Stranieri MT, Holahan MA, Sitko GR, Cook JJ, McMasters DR, McDonough CM, Sanders WM, Wallace AA, Clayton FC, Bohn D, Leonard YM, Detwiler TJ, Lynch JJ, Yan Y, Chen Z, Kuo L, Gardell SJ, Shafer JA, Vacca JP
J Med Chem 46 461-73 (2003)
Cited: 41 times
EuropePMC logo PMID: 12570369

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.

Articles - 1mu8 mentioned but not cited (2)

  1. Enhanced ligand sampling for relative protein-ligand binding free energy calculations. Kaus JW, McCammon JA. J Phys Chem B 119 6190-6197 (2015)
  2. Accelerated adaptive integration method. Kaus JW, Arrar M, McCammon JA. J Phys Chem B 118 5109-5118 (2014)


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  1. Heterocyclic N-Oxides - An Emerging Class of Therapeutic Agents. Mfuh AM, Larionov OV. Curr Med Chem 22 2819-2857 (2015)
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  3. An update on recent patents on thrombin inhibitors (2010 - 2013). Mehta AY, Jin Y, Desai UR. Expert Opin Ther Pat 24 47-67 (2014)
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