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

Medicinal Chemistry

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.

Authors

Luci, Diane; Jameson, J Brian; Yasgar, Adam; Diaz, Giovanni; Joshi, Netra; Kantz, Auric; Markham, Kate; Perry, Steve; Kuhn, Norine; Yeung, Jennifer; Kerns, Edward H; Schultz, Lena; Holinstat, Michael; Nadler, Jerry L; Taylor-Fishwick, David A; Jadhav, Ajit; Simeonov, Anton; Holman, Theodore R; Maloney, David J;

Keywords

  • 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

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