公开(公告)号：US20110105610A1

公开(公告)日：2011-05-05

申请号：US12666773

申请日：2008-07-03

申请人： Edward A. Dennis ,  Daren Stephen ,  Samuel David ,  Ruben Lopez-Vales ,  Athena Kalyvas ,  George Kokotos ,  Violetta Constantinou-Kokoton ,  Efrosini Barbayianni ,  Victoria Magrioti

发明人： Edward A. Dennis ,  Daren Stephen ,  Samuel David ,  Ruben Lopez-Vales ,  Athena Kalyvas ,  George Kokotos ,  Violetta Constantinou-Kokoton ,  Efrosini Barbayianni ,  Victoria Magrioti

IPC分类号： A61K31/221 ,  C07C229/22 ,  C12N5/071 ,  A61K31/195 ,  A61P25/00

CPC分类号： C07C235/80

摘要： Phospholipase A2 (PLA2) forms are expressed in spinal cord whose inhibition induces a potent antihyperalgesia. PLA2 inhibitor compounds are provided that include a common motif consisting of a 2-oxoamide with a hydrocarbon tail and a four carbon tether. The compounds block Group IVA calcium dependent PLA2 (cPLA2) and/or Group VIA calcium independent PLA2 (iPLA2) and/or Group V secreted PLA2 (sPLA2). Pharmaceutical compositions of compounds having cPLA2 inhibitory activity (but not iPLA2 or sPLA2 inhibitory activity) are useful in treating multiple sclerosis, while compositions of compounds having sPLA2 inhibitory activity (as well as iPLA2 and CPLA2 activity) are useful in treating spinal cord injuries (with related functional recovery).

摘要翻译： 磷脂酶A2（PLA2）形式在脊髓中表达，其抑制诱导有效的抗痛觉过敏。 提供PLA2抑制剂化合物，其包括由具有烃尾部的2-氧代酰胺和四碳系链组成的共同基序。 化合物阻断IVA类钙依赖性PLA2（cPLA2）和/或VIA钙独立PLA2（iPLA2）和/或V组分泌的PLA2（sPLA2）。 具有cPLA2抑制活性（但不是iPLA2或sPLA2抑制活性）的化合物的药物组合物可用于治疗多发性硬化，而具有sPLA2抑制活性的化合物（以及iPLA2和CPLA2活性）可用于治疗脊髓损伤（具有 相关的功能恢复）。

公开(公告)号：US08420852B2

公开(公告)日：2013-04-16

申请号：US12666773

申请日：2008-07-03

申请人： Edward A. Dennis ,  Daren Stephens ,  Samuel David ,  Ruben Lopez-Vales ,  Athena Kalyvas ,  George Kokotos ,  Violetta Constantinou-Kokotou ,  Efrosini Barbayianni ,  Victoria Magrioti

发明人： Edward A. Dennis ,  Daren Stephens ,  Samuel David ,  Ruben Lopez-Vales ,  Athena Kalyvas ,  George Kokotos ,  Violetta Constantinou-Kokotou ,  Efrosini Barbayianni ,  Victoria Magrioti

IPC分类号： C07C229/00 ,  A01N37/12 ,  A01N37/44

CPC分类号： C07C235/80

摘要： Phospholipase A2 (PLA2) forms are expressed in spinal cord whose inhibition induces a potent antihyperalgesia. PLA2 inhibitor compounds are provided that include a common motif consisting of a 2-oxoamide with a hydrocarbon tail and a four carbon tether. The compounds block Group IVA calcium dependent PLA2 (cPLA2) and/or Group VIA calcium independent PLA2 (iPLA2) and/or Group V secreted PLA2 (sPLA2). Pharmaceutical compositions of compounds having cPLA2 inhibitory activity (but not iPLA2 or sPLA2 inhibitory activity) are useful in treating multiple sclerosis, while compositions of compounds having sPLA2 inhibitory activity (as well as iPLA2 and CPLA2 activity) are useful in treating spinal cord injuries (with related functional recovery).

摘要翻译： 磷脂酶A2（PLA2）形式在脊髓中表达，其抑制诱导有效的抗痛觉过敏。 提供PLA2抑制剂化合物，其包括由具有烃尾部的2-氧代酰胺和四碳系链组成的共同基序。 化合物阻断IVA类钙依赖性PLA2（cPLA2）和/或VIA钙独立PLA2（iPLA2）和/或V组分泌的PLA2（sPLA2）。 具有cPLA2抑制活性（但不是iPLA2或sPLA2抑制活性）的化合物的药物组合物可用于治疗多发性硬化，而具有sPLA2抑制活性的化合物（以及iPLA2和CPLA2活性）可用于治疗脊髓损伤（具有 相关的功能恢复）。

公开(公告)号：US20100048727A1

公开(公告)日：2010-02-25

申请号：US12594579

申请日：2008-04-04

申请人： Samuel David ,  Athena Kalyvas ,  Ruben Lopez-Vales ,  George Kokotos ,  Violetta Constantinou-Kokotou ,  Constantinos Baskakis ,  Christoforos G. Kokotos ,  Edward A. Dennis ,  Daren Stephens

发明人： Samuel David ,  Athena Kalyvas ,  Ruben Lopez-Vales ,  George Kokotos ,  Violetta Constantinou-Kokotou ,  Constantinos Baskakis ,  Christoforos G. Kokotos ,  Edward A. Dennis ,  Daren Stephens

IPC分类号： A61K31/121 ,  C12N5/00 ,  A61K31/12 ,  C07C49/11 ,  C07C45/54 ,  C07C49/105 ,  C07C49/115 ,  C07C49/04 ,  A61P25/00 ,  A61P29/00

CPC分类号： C07C49/233 ,  C07C49/167 ,  C07C49/245 ,  C07C49/255

摘要： Novel perfluoroketone compounds of formula [I] and [Ia] are described. Also described are uses thereof, such as for inhibition of phospholipase A2 activity. Therapeutic uses thereof are also described, such as for the treatment of neural conditions and/or inflammatory conditions, such as demyelinating (e.g., multiple sclerosis) and neural injury (e.g., spinal cord injury).

摘要翻译： 描述了式[I]和[Ia]的新型全氟酮化合物。 还描述了其用途，例如用于抑制磷脂酶A2活性。 还描述了其治疗用途，例如用于治疗神经病症和/或炎性病症，例如脱髓鞘（例如多发性硬化症）和神经损伤（例如脊髓损伤）。

公开(公告)号：US20060058225A1

公开(公告)日：2006-03-16

申请号：US10516241

申请日：2003-05-30

申请人： Samuel David ,  Athena Kalyvas

发明人： Samuel David ,  Athena Kalyvas

IPC分类号： A61K38/16 ,  A61K31/739 ,  A61K48/00 ,  A61K31/66 ,  A61K31/12

CPC分类号： G01N33/6896 ,  A61K31/20 ,  A61K38/1709 ,  C12Q1/44 ,  G01N2333/918 ,  G01N2500/00

摘要： The present invention provides methods of preventing and treating neural inflammatory or demyelinating disease, such as multiple sclerosis, via an inhibition of the activity or expression of phospholipase A2. The invention further relates to methods of identifying phospholipase A2 inhibitors and their use thereof for the prevention and/or treatment of neural inflammatory or demyelinating disease. An observed increase in the amount of phospholipase A2 in neural lesions in the EAE animal model system indicates that elevated phospholipase A2 activity or levels correlate with neural inflammatory or demyelinating disease. Therefore, in a further aspect the invention provides methods for the diagnosis and prognostication of neural inflammatory or demyelinating disease, such as multiple sclerosis.

摘要翻译： 本发明通过抑制磷脂酶A 2活性或表达来提供预防和治疗神经性炎性或脱髓鞘疾病如多发性硬化的方法。 本发明还涉及鉴定磷脂酶A 2抑制剂及其在预防和/或治疗神经性炎性或脱髓鞘疾病中的用途的方法。 在EAE动物模型系统中观察到的神经损伤中磷脂酶A 2 N 2的量的增加表明升高的磷脂酶A 2活性或水平与神经性炎症或脱髓鞘疾病相关。 因此，在另一方面，本发明提供了用于神经炎性或脱髓鞘疾病如多发性硬化症的诊断和预后的方法。