Development of 2,3-dihydro-6-(3-phenoxypropyl)-2-(2-phenylethyl)-5-benzofuranol (L-670,630) as a Potent and Orally Active Inhibitor of 5-lipoxygenase

J Med Chem. 1992 Apr 3;35(7):1299-318. doi: 10.1021/jm00085a019.

Abstract

Leukotrienes are potent biological mediators of allergic and inflammatory diseases and are derived from arachidonic acid through the action of the 5-lipoxygenase. In this study, the syntheses and comparative biological activities of three series of 2,3-dihydro-2,6-disubstituted-5-benzofuranols with various substituents on position 3 are described. Compounds from each series were evaluated for their ability to inhibit the production of leukotriene B4 (LTB4) in human peripheral blood polymorphonuclear (PMN) leukocytes and the 5-lipoxygenase reaction in cell-free preparations from rat PMN leukocytes. The structure-activity relationships of each series in vitro and in vivo are presented. The bioavailability, metabolism, and toxicity profile of each series are discussed. The series with no substituent at position 3 was the most potent and among the compounds in that series 2,3-dihydro-6-(3-phenoxypropyl)-2-(2-phenylethyl)-5-benzofuranol (46, L-670,630) was chosen for further development.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Arachidonate 5-Lipoxygenase / metabolism*
  • Benzofurans / chemical synthesis*
  • Benzofurans / chemistry
  • Benzofurans / pharmacokinetics
  • Benzofurans / pharmacology
  • Biological Availability
  • Bronchoconstriction / drug effects
  • Dogs
  • Humans
  • Leukocytes, Mononuclear / enzymology
  • Leukotriene B4 / biosynthesis
  • Lipoxygenase Inhibitors / chemical synthesis*
  • Lipoxygenase Inhibitors / pharmacology
  • Male
  • Methemoglobin / metabolism
  • Microsomes, Liver / metabolism
  • Molecular Structure
  • Rats
  • Rats, Inbred Strains
  • Saimiri
  • Structure-Activity Relationship

Substances

  • Benzofurans
  • Lipoxygenase Inhibitors
  • L 670630
  • Leukotriene B4
  • Methemoglobin
  • Arachidonate 5-Lipoxygenase