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.

中文翻译：

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4-（（2-羟基-3-甲氧基苄基）氨基）苯磺酰胺衍生物作为 12-脂氧化酶的强效和选择性抑制剂的合成和构效关系研究

人类脂肪氧化酶 (LOX) 是一类含铁酶，可催化多不饱和脂肪酸氧化以提供相应的生物活性羟基二十碳四烯酸 (HETE) 代谢物。这些类二十烷酸信号分子参与了许多生理反应，例如血小板聚集、炎症和细胞增殖。我们小组对血小板型 12-( S )-LOX (12-LOX)产生了特别的兴趣，因为它在皮肤病、糖尿病、血小板止血、血栓形成和癌症中发挥了重要作用。在此，我们报告了基于 4-（（2-羟基-3-甲氧基苄基）氨基）苯磺酰胺的支架的鉴定和药物化学优化。顶级化合物，以35和36为例, 显示对 12-LOX 的 nM 效力，对相关脂肪氧化酶和环氧化酶具有出色的选择性，并具有良好的 ADME 特性。此外，这两种化合物均抑制 PAR-4 诱导的人血小板聚集和钙动员，并减少 β 细胞中的 12-HETE。