Synthesis And Structure-Activity Relationships Studies Of 4-((4-Hydroxy-3-Methoxybenzyl)Amino)Benzenesulfonamide Derivaties As Potent And Selective Inhibitors Of 12-Lipoxygenase
SYNTHESIS AND STRUCTURE-ACTIVITY RELATIONSHIPS STUDIES OF 4-((4-HYDROXY-3- METHOXYBENZYL)AMINO)BENZENESULFONAMIDE DERIVATIES AS POTENT AND SELECTIVE
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. We previously reported the discovery of ML127, a potent and selective 12-LOX inhibitor which has proven to be a valuable tool compound for researchers in the field. However, the limited tolerance for structural modification and modest PK profile for this chemotype prompted us to continue our discovery efforts toward novel 12-LOX inhibitors. 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 (ML355) and 36, display nM potency against 12- LOX and excellent selectivity over related lipoxygenases and cyclooxygenases. In addition to possessing favorable ADME properties, 35 and 36 inhibit PAR-4 induced aggregation and calcium mobilization in human platelets, and reduce 12-HETE in mouse/human beta cells.