(Methoxyalkyl)thiazoles: A New Series of Potent, Selective, and Orally Active 5-lipoxygenase Inhibitors Displaying High Enantioselectivity

J Med Chem. 1991 Jul;34(7):2176-86. doi: 10.1021/jm00111a038.

Abstract

(Methoxyalkyl)thiazoles are novel 5-lipoxygenase (5-LPO) inhibitors that are neither redox agents nor iron chelators. Consideration of a hypothetical model of the enzyme active site led to this series which is exemplified by 1-[3-(naphth-2-ylmethoxy)phenyl]-1-(thiazol-2-yl)propy l methyl ether (2d, ICI211965). 2d inhibits cell-free guinea pig 5-LPO activity, LTC4 synthesis in plasma free mouse macrophages, and LTB4 synthesis in rat and human blood (IC50s 0.1 microM, 8 nM, 0.5 microM, and 0.4 microM, respectively) but does not inhibit the synthesis of cyclooxygenase products at concentrations up to 50 microM in macrophages and 100 microM in blood. 2d is orally active in rat (ex vivo ED50 10 mg/kg in blood taken in 1 h after dosing). SAR studies show that high in vitro potency requires methoxy, thiazolyl, and naphthyl groups and depends critically on the substitution pattern. (Methoxyalkyl)thiazoles are chiral. Resolution of 1-methoxy-6-(naphth-2-ylmethoxy)-1-(thiazol-2-yl)indan (2j, ICI216800) shows that (+)-2j is 50-150-fold more potent than (-)-2j in in vitro assays. Thus, (methoxyalkyl)thiazoles are a new series of orally active, selective 5-LPO inhibitors and represent the first class of inhibitors in which inhibition is mediated by specific, enantioselective interactions with the enzyme.

Publication types

  • Comparative Study

MeSH terms

  • Administration, Oral
  • Animals
  • Chemical Phenomena
  • Chemistry
  • Enzyme Inhibitors / chemical synthesis*
  • Guinea Pigs
  • Humans
  • Leukotriene B4 / biosynthesis
  • Lipoxygenase Inhibitors*
  • Mice
  • Naphthalenes / chemical synthesis*
  • Naphthalenes / pharmacology
  • Rats
  • Structure-Activity Relationship
  • Thiazoles / chemical synthesis*
  • Thiazoles / pharmacology
  • Thromboxane B2 / biosynthesis

Substances

  • Enzyme Inhibitors
  • Lipoxygenase Inhibitors
  • Naphthalenes
  • Thiazoles
  • ICI 211965
  • Leukotriene B4
  • Thromboxane B2