公开(公告)号：US10752581B2

公开(公告)日：2020-08-25

申请号：US16289994

申请日：2019-03-01

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： David J. Maloney ,  Diane K. Luci ,  Ajit Jadhav ,  Theodore Holman ,  Jerry L. Nadler ,  Michael Holinstat ,  David Taylor-Fishwick ,  Anton Simeonov ,  Adam Yasgar ,  Steven McKenzie

IPC分类号： C07C311/44 ,  A61P7/02 ,  C07D235/30 ,  C07D263/58 ,  C07D277/82 ,  C07D277/52 ,  C07D211/28 ,  C07D213/76 ,  C07D217/02 ,  C07D217/22 ,  C07D239/69 ,  C07D261/16 ,  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.

公开(公告)号：US10266488B2

公开(公告)日：2019-04-23

申请号：US15028386

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： David J. Maloney ,  Diane K. Luci ,  Ajit Jadhav ,  Theodore Holman ,  Jerry L. Nadler ,  Michael Holinstat ,  David Taylor-Fishwick ,  Anton Simeonov ,  Adam Yasgar ,  Steven McKenzie

IPC分类号： C07D277/82 ,  C07D235/30 ,  C07D263/58 ,  C07C311/44 ,  A61P7/02 ,  C07D277/52 ,  C07D211/28 ,  C07D213/76 ,  C07D217/02 ,  C07D217/22 ,  C07D239/69 ,  C07D261/16 ,  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.

公开(公告)号：US11274077B2

公开(公告)日：2022-03-15

申请号：US16909712

申请日：2020-06-23

申请人： Eastern Virginia Medical School ,  The Regents of the Univ. of California Santa Cruz ,  The U.S. Dept of Health & Human Services ,  Thomas Jefferson University

发明人： David J. Maloney ,  Diane K. Luci ,  Ajit Jadhav ,  Theodore Holman ,  Jerry L. Nadler ,  Michael Holinstat ,  David Taylor-Fishwick ,  Anton Simeonov ,  Adam Yasgar ,  Steven McKenzie

IPC分类号： C07C311/44 ,  A61P7/02 ,  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.