Efficacious, orally bioavailable thrombin inhibitors based on 3-aminopyridinone or 3-aminopyrazinone acetamide peptidomimetic templates.


We have addressed the key deficiency of noncovalent pyridinone acetamide thrombin inhibitor L-374,087 (1), namely, its modest half-lives in animals, by making a chemically stable 3-alkylaminopyrazinone bioisostere for its 3-sulfonylaminopyridinone core. Compound 3 (L-375,378), the closest aminopyrazinone analogue of 1, has comparable selectivity and slightly decreased efficacy but significantly improved pharmacokinetics in rats, dogs, and monkeys to 1. We have developed an efficient and versatile synthesis of 3, and this compound has been chosen for further preclinical and clinical development.


Sanderson, Philip; Lyle, T A; Cutrona, K J; Dyer, D L; Dorsey, B D; McDonough, C M; Naylor-Olsen, A M; Chen, I W; Chen, Z; Cook, J J; Cooper, C M; Gardell, S J; Hare, Christy; Krueger, J A; Lewis, S D; Lin, J H; Lucas, B J; Lyle, E A; Lynch, J J; Stranieri, M T; Vastag, K; Yan, Y; Shafer, J A; Vacca, J P;


  • Aminopyridines/ chemical synthesis
  • Aminopyridines/ chemistry
  • Aminopyridines/ pharmacokinetics
  • Aminopyridines/ pharmacology
  • Animals
  • Biological Availability
  • Crystallography, X-Ray
  • Dogs
  • Macaca mulatta
  • Models, Molecular
  • Molecular Mimicry
  • Peptides/ chemistry
  • Pyrazines/ chemical synthesis
  • Pyrazines/ chemistry
  • Pyrazines/ pharmacokinetics
  • Pyrazines/ pharmacology
  • Pyridones/ chemical synthesis
  • Pyridones/ chemistry
  • Pyridones/ pharmacokinetics
  • Pyridones/ pharmacology
  • Rats
  • Structure-Activity Relationship
  • Thrombin/ antagonists & inhibitors

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