公开(公告)号：WO2007008942A2

公开(公告)日：2007-01-18

申请号：PCT/US2006/026976

申请日：2006-07-11

Applicant: AERIE PHARMACEUTICALS, INC. ,  DELONG, Mitchell, A. ,  SZNAIDMAN, Marcos, L. ,  OAKLEY, Robert, H. ,  ECKHARDT, Allen, E. ,  HUDSON, Christine ,  YINGLING, Jeffrey, D. ,  PEEL, Michael ,  RICHARDSON, Thomas, E. ,  MURRAY, Claire, Louise ,  RAO, Byappanahally, N. Narasinga ,  HEASLEY, Brian, H. ,  PATEL, Paresma, R.

Inventor： DELONG, Mitchell, A. ,  SZNAIDMAN, Marcos, L. ,  OAKLEY, Robert, H. ,  ECKHARDT, Allen, E. ,  HUDSON, Christine ,  YINGLING, Jeffrey, D. ,  PEEL, Michael ,  RICHARDSON, Thomas, E. ,  MURRAY, Claire, Louise ,  RAO, Byappanahally, N. Narasinga ,  HEASLEY, Brian, H. ,  PATEL, Paresma, R.

CPC classification number: C07D401/12 ,  C07D213/53 ,  C07D213/61 ,  C07D213/75 ,  C07D215/12 ,  C07D215/42 ,  C07D233/64 ,  C07D239/52 ,  C07D239/54 ,  C07D307/14 ,  C07D307/52 ,  C07D333/22 ,  C07D401/14

Abstract: Hydrazide compounds with GPCR desensitization inhibitory activity are provided that may be used to influence, inhibit or reduce the action of a G-protein receptor kinase. Pharmaceutical compositions including therapeutically effective amounts of the hydrazide compounds and pharmaceutically acceptable carriers are also provided. Various methods using the compounds and/or compositions to affect disease states or conditions controlled or influenced by GPCRs are also provided. Various methods using the compounds and/or compositions to affect disease states or conditions such as cancer, osteoporosis and glaucoma are also provided.

Abstract translation: 提供具有GPCR脱敏抑制活性的酰肼化合物，其可用于影响，抑制或降低G蛋白受体激酶的作用。 还提供包含治疗有效量的酰肼化合物和药学上可接受的载体的药物组合物。 还提供了使用化合物和/或组合物影响受GPCR控制或影响的疾病状态或病症的各种方法。 还提供了使用化合物和/或组合物影响疾病状态或病症如癌症，骨质疏松症和青光眼的各种方法。

公开(公告)号：WO2005012876A3

公开(公告)日：2006-04-13

申请号：PCT/US2004024572

申请日：2004-07-30

Applicant: NORAK BIOSCIENCES INC ,  OAKLEY ROBERT H

Inventor： OAKLEY ROBERT H

IPC: C07K14/705 ,  C07K19/00 ,  C12N15/62 ,  C12Q1/68 ,  G01N20060101 ,  G01N33/50 ,  G01N33/53 ,  G01N33/567

CPC classification number: G01N33/5035 ,  G01N33/5008 ,  G01N2333/726

Abstract: The methods of the present invention allow the screening of a test composition for non-receptor-specific GPCR desensitization inhibitory activity. The methods involve screening a test composition for an indication of GPCR desensitization inhibitory activity against two or more GPCRs that are different from each other. When there is an indication that a particular test composition has GPCR desensitization inhibitory activity with respect to each of the two or more GPCRs that are different from one another, then, according to the present invention, there is an indication that the test composition has non-receptor-specific GPCR desensitization inhibitory activity.

Abstract translation: 本发明的方法允许筛选非受体特异性GPCR脱敏抑制活性的测试组合物。 所述方法包括筛选测试组合物以对于彼此不同的两个或多个GPCR的GPCR脱敏抑制活性的指示。 当存在特定测试组合物相对于彼此不同的两个或更多个GPCR中的每一个具有GPCR脱敏抑制活性的指示时，根据本发明，存在测试组合物具有非 - - 受体特异性GPCR脱敏抑制活性。

公开(公告)号：WO2004038005A2

公开(公告)日：2004-05-06

申请号：PCT/US2003/033961

申请日：2003-10-24

Applicant: NORAK BIOSCIENCES, INC. ,  LOOMIS, Carson, R. ,  OAKLEY, Robert, H. ,  WANG, Shuntai ,  ECKHARDT, Allen, E.

Inventor： LOOMIS, Carson, R. ,  OAKLEY, Robert, H. ,  WANG, Shuntai ,  ECKHARDT, Allen, E.

IPC: C12N

CPC classification number: G01N33/566 ,  G01N2500/04

Abstract: Described herein are methods of identifying a transmembrane receptor (TMR) agonist and compounds identified by this method. The TMR agonist (TMRA) is capable of activating TMR signaling while exhibiting reduced TMR internalization over a control compound.

Abstract translation: 本文描述了鉴定跨膜受体（TMR）激动剂和通过该方法鉴定的化合物的方法。 TMR激动剂（TMRA）能够激活TMR信号，同时在对照化合物上显示降低的TMR内化。

公开(公告)号：WO2003097795A3

公开(公告)日：2003-11-27

申请号：PCT/US2003/014581

申请日：2003-05-12

Applicant: NORAK BIOSCIENCES, INC. ,  OAKLEY, Robert, H. ,  HUDSON, Christine, C.

Inventor： OAKLEY, Robert, H. ,  HUDSON, Christine, C.

IPC: C07K14/705

Abstract: The present invention relates to agonist-independent methods of screening for compounds that alter GPCR desensitization. Included in the present invention are cell lines containing GRKs, in which GPCRs are desensitized in the absence of agonist; the GRKs may be modified. The present invention relates to methods to determine if a GPCR is expressed at the plasma membrane, and if the GPCR has an affinity for arrestin. Modified GPCRs which have increased arrestin affinity are included in the present invention. These modified GPCRs are useful in methods to screen for compounds that alter desensitization, including both the agonist- independent methods and agonist-dependent methods described herein.

公开(公告)号：WO03097795A2

公开(公告)日：2003-11-27

申请号：PCT/US0314581

申请日：2003-05-12

Applicant: NORAK BIOSCIENCES INC ,  OAKLEY ROBERT H ,  HUDSON CHRISTINE C

Inventor： OAKLEY ROBERT H ,  HUDSON CHRISTINE C

IPC: G01N33/50 ,  C07K14/705 ,  C07K14/72 ,  C12N1/15 ,  C12N1/19 ,  C12N1/21 ,  C12N5/10 ,  C12N15/09 ,  C12Q1/02 ,  G01N33/15 ,  C12N

CPC classification number: C07K14/705 ,  C07K14/723 ,  C07K2319/033 ,  C12N9/1205 ,  G01N33/573 ,  G01N2333/726 ,  G01N2500/10

Abstract: The present invention relates to agonist-independent methods of screening for compounds that alter GPCR desensitization. Included in the present invention are cell lines containing GRKs, in which GPCRs are desensitized in the absence of agonist; the GRKs may be modified. The present invention relates to methods to determine if a GPCR is expressed at the plasma membrane, and if the GPCR has an affinity for arrestin. Modified GPCRs which have increased arrestin affinity are included in the present invention. These modified GPCRs are useful in methods to screen for compounds that alter desensitization, including both the agonist- independent methods and agonist-dependent methods described herein.

Abstract translation: 本发明涉及用于筛选改变GPCR脱敏作用的化合物的与激动剂无关的方法。 本发明包括含有GRK的细胞系，其中GPCR在不存在激动剂的情况下脱敏; 可以修改GRK。 本发明涉及确定GPCR是否在质膜上表达的方法，如果GPCR对抑制素具有亲和力。 具有增加的抑制蛋白亲和力的修饰GPCR包括在本发明中。 这些修饰的GPCR可用于筛选改变脱敏的化合物的方法，包括本文所述的与激动剂无关的方法和激动剂依赖性方法。

公开(公告)号：WO2007008942A3

公开(公告)日：2007-04-12

申请号：PCT/US2006026976

申请日：2006-07-11

Applicant: AERIE PHARMACEUTICALS INC ,  DELONG MITCHELL A ,  SZNAIDMAN MARCOS L ,  OAKLEY ROBERT H ,  ECKHARDT ALLEN E ,  HUDSON CHRISTINE ,  YINGLING JEFFREY D ,  PEEL MICHAEL ,  RICHARDSON THOMAS E ,  MURRAY CLAIRE LOUISE ,  RAO BYAPPANAHALLY N NARASINGA ,  HEASLEY BRIAN H ,  PATEL PARESMA R

Inventor： DELONG MITCHELL A ,  SZNAIDMAN MARCOS L ,  OAKLEY ROBERT H ,  ECKHARDT ALLEN E ,  HUDSON CHRISTINE ,  YINGLING JEFFREY D ,  PEEL MICHAEL ,  RICHARDSON THOMAS E ,  MURRAY CLAIRE LOUISE ,  RAO BYAPPANAHALLY N NARASINGA ,  HEASLEY BRIAN H ,  PATEL PARESMA R

IPC: C07D213/61 ,  A61K31/341 ,  A61K31/381 ,  A61K31/4164 ,  A61K31/44 ,  A61K31/47 ,  A61K31/513 ,  A61P27/02 ,  C07C251/86 ,  C07D213/36 ,  C07D215/42 ,  C07D233/88 ,  C07D239/54 ,  C07D307/52 ,  C07D333/36

CPC classification number: C07D401/12 ,  C07D213/53 ,  C07D213/61 ,  C07D213/75 ,  C07D215/12 ,  C07D215/42 ,  C07D233/64 ,  C07D239/52 ,  C07D239/54 ,  C07D307/14 ,  C07D307/52 ,  C07D333/22 ,  C07D401/14

Abstract: Hydrazide compounds with GPCR desensitization inhibitory activity are provided that may be used to influence, inhibit or reduce the action of a G-protein receptor kinase. Pharmaceutical compositions including therapeutically effective amounts of the hydrazide compounds and pharmaceutically acceptable carriers are also provided. Various methods using the compounds and/or compositions to affect disease states or conditions controlled or influenced by GPCRs are also provided. Various methods using the compounds and/or compositions to affect disease states or conditions such as cancer osteoporosis and glaucoma are also provided. (Formula (I)). A is selected from a heteroaryl group (i): wherein X 1 , X 2 , X 3 and X 4 are, independently, CH, O, S or N-R 6 , with the proviso that at least one of X 2 or X 3 is O, S or N-R 6 ; and a heteroaryl group (ii): wherein X 5 and X 9 are CH or C-halogen, X 6 and X 8 are CH, and X 7 is N, and wherein the six-membered heteroaryl group may be further fused with an unsubstituted six-member aryl group; R 1 , R 2 , R 3 , R 4 , and R 5 are, independently, hydrogen; halogen; C 1 -C 4 alkyl; amino; nitro; cyano; heteroaryl; carboxy, carbonylamino; aminosulfonyl; sulfonylamino; aminoacyl; thioalkyl; sulfonyl; acyl; heterocycle; -OR; -O-C 1 -C 4 alkyl-heterocycle; -C(O)NH-C 1 -C 4 alkyl-heterocycle; -C(O)NH-heteroaryl; -C(O)NH-aryl; or carboxylamino; wherein R is C 1 -C 4 alkyl; aryl, heteroaryl, C 1 -C 4 alkyl aryl or C 1 -C 4 alkyl heteroaryl; R 6 is H or C 1 -C 4 alkyl; R 7 is hydrogen, C 1 -C 4 alkyl or C 1 -C 4 alkoxy; and X is N-R 6 .

Abstract translation: 提供具有GPCR脱敏抑制活性的酰肼化合物，其可用于影响，抑制或降低G蛋白受体激酶的作用。 还提供包含治疗有效量的酰肼化合物和药学上可接受的载体的药物组合物。 还提供了使用化合物和/或组合物影响受GPCR控制或影响的疾病状态或病症的各种方法。 还提供了使用化合物和/或组合物影响疾病状态或病症如癌症骨质疏松症和青光眼的各种方法。 （式（I））。 A选自杂芳基（i）：其中X 1，X 2，X 3和X 4 >独立地是CH，O，S或NR 6，条件是X 2或X 3中的至少一个是O ，S或NR 6; 和杂芳基（ii）：其中X 5和X 9是CH或C-卤素，X 6和X 8 H是CH，X 7是N，并且其中六元杂芳基可以进一步与未取代的六元芳基稠合; R 1，R 2，R 3，R 4和R 5， 独立地是氢; 卤素; C 1 -C 4烷基; 氨基; 硝基; 氰基; 杂; 羧基，羰基氨基; 氨基磺酰基; 磺酰; 氨; 硫代; 磺酰基; 酰基; 杂环; -要么; -O-C _{1 -C 4 烷基 - 杂环; -C（O）NH-C 1 -C 4 烷基 - 杂环; -C（O）NH杂芳基; -C（O）NH-芳基; 或羧基氨基; 其中R是C 1 -C 4烷基; 芳基，杂芳基，C 1 -C 4烷基芳基或C 1 -C 4烷基杂芳基; R 6是H或C 1 -C 4烷基; R 7是氢，C 1 -C 4烷基或C 1 -C 4烷基或C 1 -C 4 - 烷氧基; X为N-R 6。}

公开(公告)号：WO02099381A3

公开(公告)日：2003-02-20

申请号：PCT/US0217606

申请日：2002-06-05

Applicant: UNIV DUKE ,  BARAK LAWRENCE S ,  SHETZLINE MICHAEL A ,  OAKLEY ROBERT H ,  CARON MARC G

Inventor： BARAK LAWRENCE S ,  SHETZLINE MICHAEL A ,  OAKLEY ROBERT H ,  CARON MARC G

IPC: G01N33/68 ,  C12N15/09 ,  C12Q1/00 ,  C12Q1/02 ,  C12Q1/44 ,  G01N33/49 ,  G01N33/50 ,  G01N33/74 ,  C07K14/705 ,  C07K19/00 ,  C12N15/62 ,  G01N33/52

CPC classification number: G01N33/5035 ,  G01N33/5008 ,  G01N33/5014 ,  G01N33/5091 ,  G01N33/74 ,  G01N2333/5758 ,  G01N2333/70571 ,  G01N2333/726

Abstract: The present invention is related to the detection of GPCR ligands in a test sample by using a single cell biosensor expressing a GPCR. Preferably, the test sample is derived from a biological or environmental sample. This invention may be used to detect the presence of a disease or to detect the presence of a harmful agent in the environment. Included in the present invention is an array of biosensors that detect ligands of various GPCRs.

Abstract translation: 本发明涉及通过使用表达GPCR的单细胞生物传感器检测测试样品中的GPCR配体。 优选地，测试样品来自生物或环境样品。 本发明可用于检测疾病的存在或检测环境中有害物质的存在。 本发明包括检测各种GPCR的配体的生物传感器阵列。

公开(公告)号：WO2007008926A1

公开(公告)日：2007-01-18

申请号：PCT/US2006/026947

申请日：2006-07-11

Applicant: AERIE PHARMACEUTICALS, INC. ,  DELONG, Mitchell, A. ,  SZNAIDMAN, Marcos, L. ,  OAKLEY, Robert, H. ,  ECKHARDT, Allen, E. ,  HUDSON, Christine ,  YINGLING, Jeffrey, D. ,  PEEL, Michael ,  RICHARDSON, Thomas, E. ,  MURRAY, Claire, Louise ,  RAO, Byappanahally N., Narasinga ,  HEASLEY, Brian, H. ,  PATEL, Paresma, R.

Inventor： DELONG, Mitchell, A. ,  SZNAIDMAN, Marcos, L. ,  OAKLEY, Robert, H. ,  ECKHARDT, Allen, E. ,  HUDSON, Christine ,  YINGLING, Jeffrey, D. ,  PEEL, Michael ,  RICHARDSON, Thomas, E. ,  MURRAY, Claire, Louise ,  RAO, Byappanahally N., Narasinga ,  HEASLEY, Brian, H. ,  PATEL, Paresma, R.

IPC: C07D217/02 ,  A61K31/472 ,  A61P27/06

CPC classification number: C07D217/02

Abstract: Isoquinoline compounds are provided that influence, inhibit or reduce the action of a G-protein receptor kinase . Pharmaceutical compositions including therapeutically effective amounts of the isoquinoline compounds and pharmaceutically acceptable carriers are also provided. Various methods using the compounds and/or compositions to affect disease states or conditions such as cancer, osteoporosis and glaucoma are also provided.

Abstract translation: 提供了影响，抑制或降低G蛋白受体激酶作用的异喹啉化合物。 还提供包含治疗有效量的异喹啉化合物和药学上可接受的载体的药物组合物。 还提供了使用化合物和/或组合物影响疾病状态或病症如癌症，骨质疏松症和青光眼的各种方法。

公开(公告)号：WO2005012876A2

公开(公告)日：2005-02-10

申请号：PCT/US2004/024572

申请日：2004-07-30

Applicant: NORAK BIOSCIENCES, INC. ,  OAKLEY, Robert, H.

Inventor： OAKLEY, Robert, H.

IPC: G01N

CPC classification number: G01N33/5035 ,  G01N33/5008 ,  G01N2333/726

Abstract: The methods of the present invention allow the screening of a test composition for non-receptor-specific GPCR desensitization inhibitory activity. The methods involve screening a test composition for an indication of GPCR desensitization inhibitory activity against two or more GPCRs that are different from each other. When there is an indication that a particular test composition has GPCR desensitization inhibitory activity with respect to each of the two or more GPCRs that are different from one another, then, according to the present invention, there is an indication that the test composition has non-receptor-specific GPCR desensitization inhibitory activity.

Abstract translation: 本发明的方法允许筛选非受体特异性GPCR脱敏抑制活性的测试组合物。 所述方法包括筛选测试组合物以对于彼此不同的两个或多个GPCR的GPCR脱敏抑制活性的指示。 当存在特定测试组合物相对于彼此不同的两个或更多个GPCR中的每一个具有GPCR脱敏抑制活性的指示时，根据本发明，存在测试组合物具有非 - - 受体特异性GPCR脱敏抑制活性。

公开(公告)号：WO2004038005A3

公开(公告)日：2005-02-03

申请号：PCT/US0333961

申请日：2003-10-24

Applicant: NORAK BIOSCIENCES INC ,  LOOMIS CARSON R ,  OAKLEY ROBERT H ,  WANG SHUNTAI ,  ECKHARDT ALLEN E

Inventor： LOOMIS CARSON R ,  OAKLEY ROBERT H ,  WANG SHUNTAI ,  ECKHARDT ALLEN E

IPC: C12N20060101 ,  G01N33/53 ,  G01N33/566 ,  G01N33/567

CPC classification number: G01N33/566 ,  G01N2500/04

Abstract: Described herein are methods of identifying a transmembrane receptor (TMR) agonist and compounds identified by this method. The TMR agonist (TMRA) is capable of activating TMR signaling while exhibiting reduced TMR internalization over a control compound.

Abstract translation: 本文描述了鉴定跨膜受体（TMR）激动剂和通过该方法鉴定的化合物的方法。 TMR激动剂（TMRA）能够激活TMR信号，同时在对照化合物上显示降低的TMR内化。