Novel, potent non-covalent thrombin inhibitors incorporating p(3)-lactam scaffolds

Bioorg Med Chem Lett. 2002 Mar 11;12(5):743-8. doi: 10.1016/s0960-894x(02)00010-0.

Abstract

Evolution of P(1)-argininal inhibitor prototypes led to a series of non-covalent P(3)-7-membered lactam inhibitors 1a-w, featuring novel peptidomimetic units that probe each of the S(1), S(2), and S(3) specificity pockets of thrombin. Rigid P(1)-arginine surrogates possessing a wide range of basicity (calcd pK(a)'s approximately neutral-14) were surveyed. The design, synthesis, and biological activity of these targets are presented.

Publication types

  • Evaluation Study

MeSH terms

  • Animals
  • Antithrombins / chemical synthesis*
  • Antithrombins / pharmacokinetics
  • Antithrombins / pharmacology
  • Biological Availability
  • Blood Coagulation / drug effects
  • Dogs
  • Lactams / chemical synthesis*
  • Lactams / pharmacokinetics
  • Lactams / pharmacology
  • Molecular Structure
  • Serine Endopeptidases / metabolism
  • Structure-Activity Relationship
  • Trypsin / pharmacology

Substances

  • Antithrombins
  • Lactams
  • Serine Endopeptidases
  • Trypsin