化学
脂氧合酶
羟基二十碳四烯酸
二十烷酸
生物化学
广告
酶
血小板
多不饱和脂肪酸
花生四烯酸5-脂氧合酶
体外
花生四烯酸
药理学
脂肪酸
内科学
医学
作者
Diane K. Luci,J. Brian Jameson,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
摘要
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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