(E)-3-[6-[[(2,6-dichlorophenyl)thio]methyl]-3-(2-phenylethoxy)-2- pyridinyl]-2-propenoic acid: a high-affinity leukotriene B4 receptor antagonist with oral antiinflammatory activity

J Med Chem. 1996 Sep 13;39(19):3837-41. doi: 10.1021/jm960248s.

Abstract

An extensive structure-activity study based around the high-affinity leukotriene B4 (LTB4) receptor antagonist SB 201146 (1) led to the identification of (E)-3-[6-[[(2,6-dichlorophenyl)-thio]methyl]-3-(2-phenylethoxy)-2- pyridinyl]-2-propenoic acid (3). This compound displays high affinity for the human neutrophil LTB4 receptor (Ki = 0.78 nM), blocks LTB4-induced Ca2+ mobilization with an IC50 of 6.6 +/- 1.5 nM, and demonstrates potent oral and topical antiinflammatory activity in a murine model of dermal inflammation.

MeSH terms

  • Acrylates / chemistry*
  • Acrylates / metabolism
  • Acrylates / pharmacology
  • Animals
  • Anti-Inflammatory Agents
  • Arachidonic Acid
  • Calcium / metabolism
  • Cytoplasmic Granules / drug effects
  • Cytoplasmic Granules / physiology
  • Humans
  • Leukotriene B4 / pharmacology
  • Mice
  • Mice, Inbred BALB C
  • Molecular Structure
  • Neutrophils / metabolism
  • Neutrophils / ultrastructure
  • Otitis / chemically induced
  • Otitis / drug therapy
  • Pyridines / chemistry*
  • Pyridines / metabolism
  • Pyridines / pharmacology
  • Receptors, Leukotriene B4 / antagonists & inhibitors*
  • Receptors, Leukotriene B4 / metabolism
  • Structure-Activity Relationship

Substances

  • Acrylates
  • Anti-Inflammatory Agents
  • Pyridines
  • Receptors, Leukotriene B4
  • SB 201146
  • Leukotriene B4
  • Arachidonic Acid
  • Ticolubant
  • Calcium