公开(公告)号：EP3054936A4

公开(公告)日：2017-03-29

申请号：EP14852765

申请日：2014-10-10

申请人： EASTERN VIRGINIA MEDICAL SCHOOL ,  THE REGENTS OF THE UNIV OF CALIFORNIA SANTA CRUZ ,  THE UNITED STATES OF AMERICA DEPT OF HEALTH AND HUMAN SERVICES ,  UNIV JEFFERSON

发明人： MALONEY DAVID J ,  LUCI DIANE K ,  JADHAV AJIT ,  HOLMAN THEODORE ,  NADLER JERRY L ,  HOLINSTAT MICHAEL ,  TAYLOR-FISHWICK DAVID ,  SIMEONOV ANTON ,  YASGAR ADAM ,  MCKENZIE STEVEN E

IPC分类号： A61K31/045 ,  A61K31/10 ,  A61K31/18 ,  A61P3/00 ,  A61P7/00 ,  A61P35/00 ,  C07C311/44 ,  C07D211/28 ,  C07D213/76 ,  C07D217/02 ,  C07D217/22 ,  C07D235/30 ,  C07D239/69 ,  C07D261/16 ,  C07D263/58 ,  C07D277/52 ,  C07D277/82 ,  C07D295/135 ,  C07D333/36 ,  C07D417/12 ,  C12Q1/26

CPC分类号： C07C311/44 ,  C07D211/28 ,  C07D213/76 ,  C07D217/02 ,  C07D217/22 ,  C07D235/30 ,  C07D239/69 ,  C07D261/16 ,  C07D263/58 ,  C07D277/52 ,  C07D277/82 ,  C07D295/135 ,  C07D333/36 ,  C07D417/12

摘要： Human lipoxygenases (LOXs) are a family of iron-containing enzymes involved in catalyzing 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. Platelet-type 12-(S)-LOX (12-LOX) is of particular interest because of its demonstrated role in skin diseases, diabetes, platelet hemostasis, thrombosis, and cancer. Disclosed herein is the identification and medicinal chemistry optimization of a 4-((2-hydroxy-3-methoxybenzyl)amino)benzenesulfonamide-based scaffold. The compounds display nM potency against 12-LOX and excellent selectivity over related lipoxygenases and cyclooxygenases. In addition to possessing favorable ADME properties, the compounds also inhibit PAR-4 induced aggregation and calcium mobilization in human platelets, and reduce 12-HETE in mouse/human beta cells. The compounds can also be used in methods for treating or preventing a 12-lipoxygenase mediated disease or disorder.