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

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.
Diane K Luci 1,  J Brian Jameson 2nd,  Adam Yasgar,  Giovanni Diaz,  Netra Joshi,  Auric Kantz,  Kate Markham,  Steve Perry,  Norine Kuhn,  Jennifer Yeung,  Edward H Kerns,  Lena Schultz,  Michael Holinstat,  Jerry L Nadler,  David A Taylor-Fishwick,  Ajit Jadhav,  Anton Simeonov,  Theodore R Holman,  David J Maloney
Affiliations

Affiliation

  • 1 National Center for Advancing Translational Sciences, National Institutes of Health , Rockville, Maryland, United States.
PMID: 24393039 DOI: 10.1021/jm4016476
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.

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