Omega-[(omega-arylalkyl)thienyl]alkanoic Acids: From Specific LTA4 Hydrolase Inhibitors to LTB4 Receptor Antagonists

J Med Chem. 1992 Aug 21;35(17):3170-9. doi: 10.1021/jm00095a011.

Abstract

A series of omega-[(omega-arylalkyl)thienyl]alkanoic acid isomers was prepared and a structure-activity relationship was investigated. These compounds have displayed either LTA4 hydrolase inhibition activities or LTB4 receptor binding activities, or both, depending on the relative orientation of the two side chains on the thiophene ring. Whereas the 2,5-isomers specifically exhibited LTA4 hydrolase inhibition, 3,5-isomers displayed both activities. On the other hand, the "ortho-isomers" specifically inhibited the binding of the LTB4 to its receptor. The side-chain lengths were also important for an optimal inhibition or binding activity. Substitutions on the terminal aromatic ring or on the thiophene nucleus led to small changes in both activities. The most dramatic effect was obtained by substituting the carboxylic acid side chain in the alpha-position with one or two methyl groups, which substantially enhanced the LTB4 receptor binding activity. In the most favorable case, the alpha,alpha-dimethyl derivative RP66153 was found 20-fold more potent than its linear counterpart.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Chromatography, High Pressure Liquid
  • Epoxide Hydrolases / antagonists & inhibitors*
  • Female
  • Guinea Pigs
  • Leukocytes / metabolism
  • Leukotriene A4
  • Leukotriene B4 / biosynthesis
  • Leukotriene B4 / metabolism
  • Leukotrienes / chemistry*
  • Molecular Structure
  • Receptors, Immunologic / antagonists & inhibitors*
  • Receptors, Leukotriene B4
  • Structure-Activity Relationship
  • Swine
  • Thiophenes / chemical synthesis*
  • Thiophenes / chemistry
  • Thiophenes / pharmacology

Substances

  • Leukotriene A4
  • Leukotrienes
  • Receptors, Immunologic
  • Receptors, Leukotriene B4
  • Thiophenes
  • RP 66153
  • Leukotriene B4
  • Epoxide Hydrolases
  • leukotriene A4 hydrolase