2. Academic Validation
  3. P2 pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold

P2 pyridine N-oxide thrombin inhibitors: a novel peptidomimetic scaffold

  • Bioorg Med Chem Lett. 2005 Jun 2;15(11):2771-5. doi: 10.1016/j.bmcl.2005.03.110.
Philippe G Nantermet 1,  Christopher S Burgey,  Kyle A Robinson,  Janetta M Pellicore,  Christina L Newton,  James Z Deng,  Harold G Selnick,  S Dale Lewis,  Bobby J Lucas,  Julie A Krueger,  Cynthia Miller-Stein,  Rebecca B White,  Bradley Wong,  Daniel R McMasters,  Audrey A Wallace,  Joseph J Lynch Jr,  Youwei Yan,  Zhongguo Chen,  Lawrence Kuo,  Stephen J Gardell,  Jules A Shafer,  Joseph P Vacca,  Terry A Lyle
Affiliations

Affiliation

  • 1 Department of Medicinal Chemistry, Merck Research Laboratories, West Point, PA 19486, USA. [email protected]
PMID: 15911253 DOI: 10.1016/j.bmcl.2005.03.110
Abstract

In this study, we have demonstrated that the critical hydrogen bonding motif of the established 3-aminopyrazinone Thrombin inhibitors can be effectively mimicked by a 2-aminopyridine N-oxide. As this peptidomimetic core is more resistant toward oxidative metabolism, it also overcomes the metabolic liability associated with the pyrazinones. An optimization study of the P(1) benzylamide delivered the potent Thrombin Inhibitor 21 (K(i) = 3.2 nM, 2xaPTT = 360 nM), which exhibited good plasma levels and half-life after oral dosing in the dog (C(max) = 2.6 microM, t(1/2) = 4.5 h).

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