Synthesis and Structure–Activity Relationship Studies of 4-((2-Hydroxy-3-methoxybenzyl)amino)benzenesulfonamide Derivatives as Potent and Selective Inhibitors of 12-Lipoxygenase
| Autor: | David J. Maloney, Anton Simeonov, Adam Yasgar, Giovanni Diaz, Edward H. Kerns, J. Brian Jameson, Diane K. Luci, Michael Holinstat, Theodore R. Holman, David A. Taylor-Fishwick, Kate Markham, Norine Kuhn, Ajit Jadhav, Netra Joshi, Steve Perry, Jennifer Yeung, Lena Schultz, Auric Kantz, Jerry L. Nadler |
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| Rok vydání: | 2014 |
| Předmět: |
Blood Platelets
Platelet Aggregation Stereochemistry Biological Availability Arachidonate 12-Lipoxygenase Article Islets of Langerhans Mice Structure-Activity Relationship Lipoxygenase Drug Discovery Benzene Derivatives Animals Humans Structure–activity relationship Platelet Lipoxygenase Inhibitors ADME chemistry.chemical_classification Sulfonamides biology Chemistry Hydroxyeicosatetraenoic acid Enzyme Eicosanoid Biochemistry biology.protein Molecular Medicine Calcium lipids (amino acids peptides and proteins) Polyunsaturated fatty acid |
| Zdroj: | Journal of Medicinal Chemistry. 57:495-506 |
| ISSN: | 1520-4804 0022-2623 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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