A novel series of potent and selective small molecule inhibitors of the complement component C1s

Bioorg Med Chem Lett. 2004 Jun 21;14(12):3043-7. doi: 10.1016/j.bmcl.2004.04.034.

Abstract

Activation of the classical pathway of complement has been implicated in disease states such as hereditary angioedema, ischemia-reperfusion injury and acute transplant rejection. The trypsin-like serine protease C1s represents a pivotal upstream point of control in the classical pathway of complement activation and is therefore likely to be a useful target in the therapeutic intervention of these disease states. A series of thiopheneamidine-based inhibitors of C1s has been optimized to give a 70 nM inhibitor that inhibits the classical pathway of complement activation in vitro.

MeSH terms

  • Binding Sites / physiology
  • Complement C1 / metabolism
  • Complement Inactivator Proteins / chemical synthesis*
  • Complement Inactivator Proteins / pharmacology
  • Complement Pathway, Classical / drug effects*
  • Complement Pathway, Classical / physiology
  • Humans
  • Myocardial Ischemia / drug therapy
  • Myocardial Ischemia / enzymology
  • Pyrazoles / chemical synthesis*
  • Pyrazoles / pharmacology
  • Serine Endopeptidases / metabolism*
  • Serine Proteinase Inhibitors / chemical synthesis*
  • Serine Proteinase Inhibitors / pharmacology
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / pharmacology
  • Thiophenes / chemical synthesis*
  • Thiophenes / pharmacology

Substances

  • Complement C1
  • Complement Inactivator Proteins
  • Pyrazoles
  • Serine Proteinase Inhibitors
  • Thiazoles
  • Thiophenes
  • Serine Endopeptidases