公开(公告)号：EP3054936A1

公开(公告)日：2016-08-17

申请号：EP14852765.8

申请日：2014-10-10

申请人： Eastern Virginia Medical School ,  The Regents of The University of California Santa Cruz ,  The United States of America Department of Health and Human Services ,  Thomas Jefferson University

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 ,  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.

摘要翻译： 人类脂氧合酶（LOX）是涉及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）代谢物的含铁酶的家族。 这些类花生酸信号分子参与许多生理反应，例如血小板聚集，炎症和细胞增殖。 由于其在皮肤疾病，糖尿病，血小板止血，血栓形成和癌症中的作用，血小板型12-（S）-LOX（12-LOX）是特别有意义的。 本文公开了4 - （（2-羟基-3-甲氧基苄基）氨基）苯磺酰胺类支架的鉴定和药物化学优化。 该化合物显示出对12-LOX的nM效力和对相关脂氧合酶和环加氧酶的优异选择性。 除了具有良好的ADME特性外，化合物还抑制人血小板中PAR-4诱导的聚集和钙迁移，并减少小鼠/人β细胞中的12-HETE。 该化合物也可用于治疗或预防12-脂肪氧合酶介导的疾病或病症的方法。

公开(公告)号：EP3036226B1

公开(公告)日：2020-01-08

申请号：EP14837235.2

申请日：2014-08-22

申请人： The General Hospital Corporation ,  The Regents of The University of California Santa Cruz ,  The U.S.A. as represented by the Secretary, Department of Health and Human Services

发明人： VAN LEYEN, Klaus ,  HOLMAN, Theodore R. ,  MALONEY, David J. ,  JADHAV, Ajit ,  SIMEONOV, Anton ,  RAI, Ganesha

IPC分类号： C07D263/48 ,  C07D277/42 ,  C07D413/04 ,  C07D417/04 ,  A61K31/421 ,  A61K31/422 ,  A61K31/426 ,  A61K31/427 ,  A61K31/4709 ,  A61K31/4725 ,  A61P9/00 ,  A61P9/10 ,  A61P25/28 ,  A61P35/00

公开(公告)号：EP2571853A1

公开(公告)日：2013-03-27

申请号：EP11721629.1

申请日：2011-05-18

申请人： The U.S.A. as represented by the Secretary, Department of Health and Human Services ,  The Regents of the University of California ,  Eastern Virginia Medical School ,  Thomas Jefferson University

发明人： MALONEY, David J. ,  HOLMAN, Theodore ,  JADHAV, Ajit ,  SIMEONOV, Anton ,  BANTUKALLU, Ganesha Rai ,  NADLER, Jerry L. ,  HOLINSTAT, Michael

IPC分类号： C07D215/28 ,  C07D215/38 ,  C07D405/06 ,  C07D409/06 ,  A61K31/47 ,  A61K31/4709 ,  A61K31/496 ,  A61P3/10 ,  A61P9/00

CPC分类号： C07D409/04 ,  C07D215/28 ,  C07D215/38 ,  C07D405/06 ,  C07D409/06

摘要： Disclosed are inhibitors of human 12-lipoxygenase of Formula (I) or (II), wherein R
1 , R
2 , R
3 , and R
4 are as defined herein, that are useful in treating or preventing a 12-lipoxygenase mediated disease or disorder, e.g., diabetes. Also disclosed are a composition comprising a pharmaceutically acceptable carrier and at least one inhibitor of the invention, and a method of treating or preventing such disease or disorder in a mammal.