Synthesis and structure-activity relationship studies of 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide derivatives as potent and selective inhibitors of 12-lipoxygenase

J Med Chem. 2014 Jan 23;57(2):495-506. doi: 10.1021/jm4016476. Epub 2014 Jan 6.

Abstract

Human lipoxygenases (LOXs) are a family of iron-containing enzymes which catalyze the oxidation of polyunsaturated fatty acids to provide the corresponding bioactive hydroxyeicosatetraenoic acid (HETE) metabolites. These eicosanoid signaling molecules are involved in a number of physiologic responses such as platelet aggregation, inflammation, and cell proliferation. Our group has taken a particular interest in platelet-type 12-(S)-LOX (12-LOX) because of its demonstrated role in skin diseases, diabetes, platelet hemostasis, thrombosis, and cancer. Herein, we report the identification and medicinal chemistry optimization of a 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide-based scaffold. Top compounds, exemplified by 35 and 36, display nM potency against 12-LOX, excellent selectivity over related lipoxygenases and cyclooxygenases, and possess favorable ADME properties. In addition, both compounds inhibit PAR-4 induced aggregation and calcium mobilization in human platelets and reduce 12-HETE in β-cells.

Publication types

  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Arachidonate 12-Lipoxygenase / metabolism*
  • Benzene Derivatives / chemical synthesis*
  • Benzene Derivatives / chemistry
  • Benzene Derivatives / pharmacology
  • Biological Availability
  • Blood Platelets / drug effects
  • Blood Platelets / metabolism
  • Calcium / metabolism
  • Humans
  • Islets of Langerhans / drug effects
  • Islets of Langerhans / enzymology
  • Lipoxygenase Inhibitors / chemical synthesis*
  • Lipoxygenase Inhibitors / chemistry
  • Lipoxygenase Inhibitors / pharmacology
  • Mice
  • Platelet Aggregation / drug effects
  • Structure-Activity Relationship
  • Sulfonamides / chemical synthesis*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology

Substances

  • Benzene Derivatives
  • Lipoxygenase Inhibitors
  • Sulfonamides
  • Arachidonate 12-Lipoxygenase
  • Calcium