公开(公告)号：US08883473B2

公开(公告)日：2014-11-11

申请号：US13533131

申请日：2012-06-26

申请人： Kristi A. Leonard ,  Richard Scott Alexander ,  Joseph Kent Barbay ,  Roger F. Bone ,  Carl Crysler ,  Ingrid Christa Deckman ,  Paul F. Jackson ,  Lawrence C. Kuo ,  Frank A. Lewandowski ,  Diane M. Maguire ,  Carl Manthey ,  Cynthia M. Milligan ,  Beverley Moore ,  Kenneth J. Rhodes ,  Robert H. Scannevin ,  Celine Schalk-Hihi ,  Barry Springer ,  John C. Spurlino ,  Matthew J. Todd ,  Brett A. Tounge ,  Aihua Wang

发明人： Kristi A. Leonard ,  Richard Scott Alexander ,  Joseph Kent Barbay ,  Roger F. Bone ,  Carl Crysler ,  Ingrid Christa Deckman ,  Paul F. Jackson ,  Lawrence C. Kuo ,  Frank A. Lewandowski ,  Diane M. Maguire ,  Carl Manthey ,  Cynthia M. Milligan ,  Beverley Moore ,  Kenneth J. Rhodes ,  Robert H. Scannevin ,  Celine Schalk-Hihi ,  Barry Springer ,  John C. Spurlino ,  Matthew J. Todd ,  Brett A. Tounge ,  Aihua Wang

IPC分类号： A61K31/4439 ,  A61K31/427 ,  A61P19/02 ,  A61K31/425

CPC分类号： A61K31/425 ,  A61K31/4439 ,  C07K2299/00 ,  G01N2333/96486

摘要： The present invention includes a crystal comprising a complex of the pro form of a matrix metalloprotease (proMMP) and a small-molecule allosteric processing inhibitor that inhibits that activation of the proMMP, methods for identifying small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP, and methods of treatment using small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP. The present invention relates to the crystal structure of a complex of proMMP9 bound to a small-molecule allosteric processing inhibitor that inhibits activation of proMMP9. The invention further relates to the use of the methods and the crystal and related structural information for designing, selecting and/or optimizing small-molecule allosteric processing inhibitors that inhibit activation of proMMP9 and proMMP9 homologues. The present invention also relates to the use of small-molecule allosteric processing inhibitors for the treatment of diseases mediated by inappropriate matrix metalloproteinase (MMP) activity.

摘要翻译： 本发明包括晶体，其包含基质金属蛋白酶（proMMP）的形式的复合物和抑制该proMMP活化的小分子变构加工抑制剂，用于鉴定抑制激活的小分子变构加工抑制剂的方法 proMMP和使用抑制proMMP激活的小分子变构加工抑制剂的治疗方法。 本发明涉及与抑制proMMP9激活的小分子变构加工抑制剂结合的proMMP9的复合物的晶体结构。 本发明还涉及用于设计，选择和/或优化抑制proMMP9和proMMP9同源物激活的小分子变构加工抑制剂的方法和结晶及相关结构信息的使用。 本发明还涉及小分子变构加工抑制剂用于治疗由不适当的基质金属蛋白酶（MMP）活性介导的疾病的用途。

公开(公告)号：US20130040994A1

公开(公告)日：2013-02-14

申请号：US13533131

申请日：2012-06-26

申请人： Kristi A. Leonard ,  Richard Scott Alexander ,  Joseph Kent Barbay ,  Roger F. Bone ,  Carl Crysler ,  Ingrid Christa Deckman ,  Paul F. Jackson ,  Lawrence C. Kuo ,  Frank A. Lewandowski ,  Diane M. Maguire ,  Carl Manthey ,  Cynthia M. Milligan ,  Beverley Moore ,  Kenneth J. Rhodes ,  Robert H. Scannevin ,  Celine Schalk-Hihi ,  Barry Springer ,  John C. Spurlino ,  Matthew J. Todd ,  Brett Andrew Tongue ,  Aihua Wang

发明人： Kristi A. Leonard ,  Richard Scott Alexander ,  Joseph Kent Barbay ,  Roger F. Bone ,  Carl Crysler ,  Ingrid Christa Deckman ,  Paul F. Jackson ,  Lawrence C. Kuo ,  Frank A. Lewandowski ,  Diane M. Maguire ,  Carl Manthey ,  Cynthia M. Milligan ,  Beverley Moore ,  Kenneth J. Rhodes ,  Robert H. Scannevin ,  Celine Schalk-Hihi ,  Barry Springer ,  John C. Spurlino ,  Matthew J. Todd ,  Brett Andrew Tongue ,  Aihua Wang

IPC分类号： A61K31/427 ,  A61P35/00 ,  A61P19/02 ,  A61P9/00 ,  A61P1/04 ,  A61P9/12 ,  A61P11/00 ,  A61P1/02 ,  A61P17/02 ,  A61P1/16 ,  A61P9/10 ,  A61P25/00 ,  A61P11/06 ,  A61P13/12 ,  A61P25/06 ,  C12N9/99 ,  A61K31/4439

CPC分类号： A61K31/425 ,  A61K31/4439 ,  C07K2299/00 ,  G01N2333/96486

摘要： The present invention includes a crystal comprising a complex of the pro form of a matrix metalloprotease (proMMP) and a small-molecule allosteric processing inhibitor that inhibits that activation of the proMMP, methods for identifying small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP, and methods of treatment using small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP. The present invention relates to the crystal structure of a complex of proMMP9 bound to a small-molecule allosteric processing inhibitor that inhibits activation of proMMP9. The invention further relates to the use of the methods and the crystal and related structural information for designing, selecting and/or optimizing small-molecule allosteric processing inhibitors that inhibit activation of proMMP9 and proMMP9 homologues. The present invention also relates to the use of small-molecule allosteric processing inhibitors for the treatment of diseases mediated by inappropriate matrix metalloproteinase (MMP) activity.

摘要翻译： 本发明包括晶体，其包含基质金属蛋白酶（proMMP）的形式的复合物和抑制该proMMP活化的小分子变构加工抑制剂，用于鉴定抑制激活的小分子变构加工抑制剂的方法 proMMP和使用抑制proMMP激活的小分子变构加工抑制剂的治疗方法。 本发明涉及与抑制proMMP9激活的小分子变构加工抑制剂结合的proMMP9的复合物的晶体结构。 本发明还涉及用于设计，选择和/或优化抑制proMMP9和proMMP9同源物激活的小分子变构加工抑制剂的方法和结晶及相关结构信息的使用。 本发明还涉及小分子变构加工抑制剂用于治疗由不适当的基质金属蛋白酶（MMP）活性介导的疾病的用途。

公开(公告)号：US08798939B2

公开(公告)日：2014-08-05

申请号：US13533201

申请日：2012-06-26

申请人： Kristi A. Leonard ,  Richard Scott Alexander ,  Joseph Kent Barbay ,  Roger F. Bone ,  Ingrid Christa Deckman ,  Paul F. Jackson ,  Lawrence C. Kuo ,  Frank A. Lewandowski ,  Diane M. Maguire ,  Cynthia M. Milligan ,  Kenneth J. Rhodes ,  Robert H. Scannevin ,  Celine Schalk-Hihi ,  Barry Springer ,  John C. Spurlino ,  Matthew J. Todd ,  Brett A. Tounge ,  Aihua Wang

发明人： Kristi A. Leonard ,  Richard Scott Alexander ,  Joseph Kent Barbay ,  Roger F. Bone ,  Ingrid Christa Deckman ,  Paul F. Jackson ,  Lawrence C. Kuo ,  Frank A. Lewandowski ,  Diane M. Maguire ,  Cynthia M. Milligan ,  Kenneth J. Rhodes ,  Robert H. Scannevin ,  Celine Schalk-Hihi ,  Barry Springer ,  John C. Spurlino ,  Matthew J. Todd ,  Brett A. Tounge ,  Aihua Wang

IPC分类号： G01N33/48 ,  G01N33/50 ,  G01N31/00

CPC分类号： G06F19/706 ,  C12N9/6491 ,  G06F19/16 ,  G06F19/18 ,  Y02A90/26

摘要： The present invention includes a crystal comprising a complex of the pro form of a matrix metalloprotease (proMMP) and a small-molecule allosteric processing inhibitor that inhibits that activation of the proMMP, methods for identifying small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP, and methods of treatment using small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP. The present invention relates to the crystal structure of a complex of proMMP9 bound to a small-molecule allosteric processing inhibitor that inhibits activation of proMMP9. The invention further relates to the use of the methods and the crystal and related structural information for designing, selecting and/or optimizing small-molecule allosteric processing inhibitors that inhibit activation of proMMP9 and proMMP9 homologues. The present invention also relates to the use of small-molecule allosteric processing inhibitors for the treatment of diseases mediated by inappropriate matrix metalloproteinase (MMP) activity.

摘要翻译： 本发明包括晶体，其包含基质金属蛋白酶（proMMP）的形式的复合物和抑制该proMMP活化的小分子变构加工抑制剂，用于鉴定抑制激活的小分子变构加工抑制剂的方法 proMMP和使用抑制proMMP激活的小分子变构加工抑制剂的治疗方法。 本发明涉及与抑制proMMP9激活的小分子变构加工抑制剂结合的proMMP9的复合物的晶体结构。 本发明还涉及用于设计，选择和/或优化抑制proMMP9和proMMP9同源物激活的小分子变构加工抑制剂的方法和结晶及相关结构信息的使用。 本发明还涉及小分子变构加工抑制剂用于治疗由不适当的基质金属蛋白酶（MMP）活性介导的疾病的用途。

公开(公告)号：US08753857B2

公开(公告)日：2014-06-17

申请号：US13533108

申请日：2012-06-26

申请人： Kristi A. Leonard ,  Richard Scott Alexander ,  Joseph Kent Barbay ,  Roger F. Bone ,  Ingrid Christa Deckman ,  Paul F. Jackson ,  Lawrence C. Kuo ,  Frank A. Lewandowski ,  Diane M. Maguire ,  Cynthia M. Milligan ,  Kenneth J. Rhodes ,  Robert H. Scannevin ,  Celine Schalk-Hihi ,  Barry Springer ,  John C. Spurlino ,  Matthew J. Todd ,  Brett A. Tounge ,  Aihua Wang

发明人： Kristi A. Leonard ,  Richard Scott Alexander ,  Joseph Kent Barbay ,  Roger F. Bone ,  Ingrid Christa Deckman ,  Paul F. Jackson ,  Lawrence C. Kuo ,  Frank A. Lewandowski ,  Diane M. Maguire ,  Cynthia M. Milligan ,  Kenneth J. Rhodes ,  Robert H. Scannevin ,  Celine Schalk-Hihi ,  Barry Springer ,  John C. Spurlino ,  Matthew J. Todd ,  Brett A. Tounge ,  Aihua Wang

IPC分类号： C12N9/00 ,  G01N31/00

CPC分类号： C12N9/6491 ,  C12Y304/24017 ,  C12Y304/24035

摘要： The present invention includes a crystal comprising a complex of the pro form of a matrix metalloprotease (proMMP) and a small-molecule allosteric processing inhibitor that inhibits that activation of the proMMP, methods for identifying small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP, and methods of treatment using small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP. The present invention relates to the crystal structure of a complex of proMMP9 bound to a small-molecule allosteric processing inhibitor that inhibits activation of proMMP9. The invention further relates to the use of the methods and the crystal and related structural information for designing, selecting and/or optimizing small-molecule allosteric processing inhibitors that inhibit activation of proMMP9 and proMMP9 homologues. The present invention also relates to the use of small-molecule allosteric processing inhibitors for the treatment of diseases mediated by inappropriate matrix metalloproteinase (MMP) activity.

摘要翻译： 本发明包括晶体，其包含基质金属蛋白酶（proMMP）的形式的复合物和抑制该proMMP活化的小分子变构加工抑制剂，用于鉴定抑制激活的小分子变构加工抑制剂的方法 proMMP和使用抑制proMMP激活的小分子变构加工抑制剂的治疗方法。 本发明涉及与抑制proMMP9激活的小分子变构加工抑制剂结合的proMMP9的复合物的晶体结构。 本发明还涉及用于设计，选择和/或优化抑制proMMP9和proMMP9同源物激活的小分子变构加工抑制剂的方法和结晶及相关结构信息的使用。 本发明还涉及小分子变构加工抑制剂用于治疗由不适当的基质金属蛋白酶（MMP）活性介导的疾病的用途。

公开(公告)号：US20130166268A1

公开(公告)日：2013-06-27

申请号：US13533201

申请日：2012-06-26

申请人： Kristi A. Leonard ,  Richard Scott Alexander ,  Joseph Kent Barbay ,  Roger F. Bone ,  Ingrid Christa Deckman ,  Paul F. Jackson ,  Lawrence C. Kuo ,  Frank A. Lewandowski ,  Diane M. Maguire ,  Cynthia M. Milligan ,  Kenneth J. Rhodes ,  Robert H. Scannevin ,  Celine Schalk-Hihi ,  Barry Springer ,  John C. Spurlino ,  Matthew J. Todd ,  Brett Andrew Tongue ,  Aihua Wang

发明人： Kristi A. Leonard ,  Richard Scott Alexander ,  Joseph Kent Barbay ,  Roger F. Bone ,  Ingrid Christa Deckman ,  Paul F. Jackson ,  Lawrence C. Kuo ,  Frank A. Lewandowski ,  Diane M. Maguire ,  Cynthia M. Milligan ,  Kenneth J. Rhodes ,  Robert H. Scannevin ,  Celine Schalk-Hihi ,  Barry Springer ,  John C. Spurlino ,  Matthew J. Todd ,  Brett Andrew Tongue ,  Aihua Wang

IPC分类号： G06F19/12

CPC分类号： G06F19/706 ,  C12N9/6491 ,  G06F19/16 ,  G06F19/18 ,  Y02A90/26

摘要： The present invention includes a crystal comprising a complex of the pro form of a matrix metalloprotease (proMMP) and a small-molecule allosteric processing inhibitor that inhibits that activation of the proMMP, methods for identifying small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP, and methods of treatment using small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP. The present invention relates to the crystal structure of a complex of proMMP9 bound to a small-molecule allosteric processing inhibitor that inhibits activation of proMMP9. The invention further relates to the use of the methods and the crystal and related structural information for designing, selecting and/or optimizing small-molecule allosteric processing inhibitors that inhibit activation of proMMP9 and proMMP9 homologues. The present invention also relates to the use of small-molecule allosteric processing inhibitors for the treatment of diseases mediated by inappropriate matrix metalloproteinase (MMP) activity.

摘要翻译： 本发明包括晶体，其包含基质金属蛋白酶（proMMP）的形式的复合物和抑制该proMMP的激活的小分子变构的加工抑制剂，用于鉴定抑制激活的小分子变构加工抑制剂的方法 proMMP和使用抑制proMMP激活的小分子变构加工抑制剂的治疗方法。 本发明涉及与抑制proMMP9激活的小分子变构加工抑制剂结合的proMMP9的复合物的晶体结构。 本发明还涉及用于设计，选择和/或优化抑制proMMP9和proMMP9同源物激活的小分子变构加工抑制剂的方法和结晶及相关结构信息的使用。 本发明还涉及小分子变构加工抑制剂用于治疗由不适当的基质金属蛋白酶（MMP）活性介导的疾病的用途。

公开(公告)号：US20130040360A1

公开(公告)日：2013-02-14

申请号：US13533108

申请日：2012-06-26

申请人： Kristi A. Leonard ,  Richard Scott Alexander ,  Joseph Kent Barbay ,  Roger F. Bone ,  Ingrid Christa Deckman ,  Paul F. Jackson ,  Lawrence C. Kuo ,  Frank A. Lewandowski ,  Diane M. Maguire ,  Cynthia M. Milligan ,  Kenneth J. Rhodes ,  Robert H. Scannevin ,  Celine Schalk-Hihi ,  Barry Springer ,  John C. Spurlino ,  Matthew J. Todd ,  Brett Andrew Tongue ,  Aihua Wang

发明人： Kristi A. Leonard ,  Richard Scott Alexander ,  Joseph Kent Barbay ,  Roger F. Bone ,  Ingrid Christa Deckman ,  Paul F. Jackson ,  Lawrence C. Kuo ,  Frank A. Lewandowski ,  Diane M. Maguire ,  Cynthia M. Milligan ,  Kenneth J. Rhodes ,  Robert H. Scannevin ,  Celine Schalk-Hihi ,  Barry Springer ,  John C. Spurlino ,  Matthew J. Todd ,  Brett Andrew Tongue ,  Aihua Wang

IPC分类号： C12N9/96

CPC分类号： C12N9/6491 ,  C12Y304/24017 ,  C12Y304/24035

摘要： The present invention includes a crystal comprising a complex of the pro form of a matrix metalloprotease (proMMP) and a small-molecule allosteric processing inhibitor that inhibits that activation of the proMMP, methods for identifying small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP, and methods of treatment using small-molecule allosteric processing inhibitors that inhibit the activation of a proMMP. The present invention relates to the crystal structure of a complex of proMMP9 bound to a small-molecule allosteric processing inhibitor that inhibits activation of proMMP9. The invention further relates to the use of the methods and the crystal and related structural information for designing, selecting and/or optimizing small-molecule allosteric processing inhibitors that inhibit activation of proMMP9 and proMMP9 homologues. The present invention also relates to the use of small-molecule allosteric processing inhibitors for the treatment of diseases mediated by inappropriate matrix metalloproteinase (MMP) activity.

公开(公告)号：US07049094B2

公开(公告)日：2006-05-23

申请号：US10051841

申请日：2002-01-17

申请人： Kathleen H. Young ,  Kenneth J. Rhodes

发明人： Kathleen H. Young ,  Kenneth J. Rhodes

IPC分类号： C12N15/00 ,  C12N15/12 ,  C12N15/63 ,  C07K14/00 ,  C07H21/04

CPC分类号： C12Q1/025 ,  G01N2333/705

摘要： Methods and compositions for identifying compounds which disrupt the functional interaction of an intracellular receptor region of an α-subunit of a voltage-gated ion channel and an amino-terminal inactivation region of an ion channel protein are disclosed. Compounds that disrupt the functional or binding interaction of these two regions have significant modulatory effects on ion channel activity, and thus are likely to be useful for treating and/or preventing a wide variety of diseases and pathological conditions associated with ion channel dysfunction. Such conditions include, for example, neurological disorders, cardiac diseases, metabolic diseases, tumor-driven diseases, and autoimmune diseases.

公开(公告)号：US20120141456A1

公开(公告)日：2012-06-07

申请号：US13131231

申请日：2009-11-24

申请人： Sha Mi ,  Kenneth J. Rhodes ,  R. Blake Pepinsky

发明人： Sha Mi ,  Kenneth J. Rhodes ,  R. Blake Pepinsky

IPC分类号： A61K39/395 ,  C12N5/071 ,  A61P25/00 ,  A61K31/713 ,  C07K16/28 ,  C07H21/04

CPC分类号： C07K16/2878 ,  A61K31/7088 ,  A61K31/713 ,  A61K38/00 ,  A61K38/177 ,  A61K39/39541 ,  A61K2039/505 ,  C07K14/00 ,  C07K14/70578 ,  C07K2317/34 ,  C07K2317/56 ,  C07K2317/565 ,  C07K2317/76 ,  C07K2319/30 ,  C12N15/111 ,  C12N15/1138 ,  C12N2310/14

摘要： The present invention relates to Death Receptor-6 (DR6) proteins which are members of the tumor necrosis factor (TNF) receptor family, and have now been shown to be important for regulating apoptosis in cells of the nervous system. In addition, it has been discovered that p75 is a ligand for DR6. As a result, this invention relates to methods for inhibiting the interaction of DR6 and p75 using DR6 and/or p75 antagonists. In addition, the methods described herein include methods of promoting survival of cells of the nervous system using DR6 antagonists, optionally in combination with p75 antagonists, and methods of treating neurodegenerative conditions by the administration of a DR6 antagonists, optionally in combination with a p75 antagonist.

摘要翻译： 本发明涉及作为肿瘤坏死因子（TNF）受体家族成员的死亡受体-6（DR6）蛋白，现在已被证明对调节神经系统细胞凋亡是重要的。 此外，已经发现p75是DR6的配体。 因此，本发明涉及使用DR6和/或p75拮抗剂抑制DR6和p75相互作用的方法。 此外，本文所述的方法包括使用DR6拮抗剂（任选与p75拮抗剂组合）促进神经系统细胞存活的方法，以及任选地与p75拮抗剂组合施用DR6拮抗剂治疗神经变性病症的方法 。

公开(公告)号：US08501178B2

公开(公告)日：2013-08-06

申请号：US13131231

申请日：2009-11-24

申请人： Sha Mi ,  Kenneth J. Rhodes ,  R. Blake Pepinsky

发明人： Sha Mi ,  Kenneth J. Rhodes ,  R. Blake Pepinsky

IPC分类号： A61K39/00 ,  A61K39/395

CPC分类号： C07K16/2878 ,  A61K31/7088 ,  A61K31/713 ,  A61K38/00 ,  A61K38/177 ,  A61K39/39541 ,  A61K2039/505 ,  C07K14/00 ,  C07K14/70578 ,  C07K2317/34 ,  C07K2317/56 ,  C07K2317/565 ,  C07K2317/76 ,  C07K2319/30 ,  C12N15/111 ,  C12N15/1138 ,  C12N2310/14

摘要： The present invention relates to Death Receptor-6 (DR6) proteins which are members of the tumor necrosis factor (TNF) receptor family, and have now been shown to be important for regulating apoptosis in cells of the nervous system. In addition, it has been discovered that p75 is a ligand for DR6. As a result, this invention relates to methods for inhibiting the interaction of DR6 and p75 using DR6 and/or p75 antagonists. In addition, the methods described herein include methods of promoting survival of cells of the nervous system using DR6 antagonists, optionally in combination with p75 antagonists, and methods of treating neurodegenerative conditions by the administration of a DR6 antagonists, optionally in combination with a p75 antagonist.

摘要翻译： 本发明涉及作为肿瘤坏死因子（TNF）受体家族成员的死亡受体-6（DR6）蛋白，现在已被证明对调节神经系统细胞凋亡是重要的。 此外，已经发现p75是DR6的配体。 因此，本发明涉及使用DR6和/或p75拮抗剂抑制DR6和p75相互作用的方法。 此外，本文所述的方法包括使用DR6拮抗剂（任选与p75拮抗剂组合）促进神经系统细胞存活的方法，以及任选地与p75拮抗剂组合施用DR6拮抗剂治疗神经变性病症的方法 。

公开(公告)号：US07049083B2

公开(公告)日：2006-05-23

申请号：US10051843

申请日：2002-01-17

申请人： Kathleen H. Young ,  Kenneth J. Rhodes

发明人： Kathleen H. Young ,  Kenneth J. Rhodes

IPC分类号： C12N15/63 ,  C12N1/15 ,  C12N1/16 ,  C12N15/00 ,  G01N33/566

CPC分类号： C12Q1/025 ,  G01N2333/705

摘要： Methods and compositions for identifying compounds which disrupt the functional interaction of an intracellular receptor region of an α-subunit of a voltage-gated ion channel and an amino-terminal inactivation region of an ion channel protein are disclosed. Compounds that disrupt the functional or binding interaction of these two regions have significant modulatory effects on ion channel activity, and thus are likely to be useful for treating and/or preventing a wide variety of diseases and pathological conditions associated with ion channel dysfunction. Such conditions include, for example, neurological disorders, cardiac diseases, metabolic diseases, tumor-driven diseases, and autoimmune diseases.