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Discovery of 4-((3′R,4′S,5′R)-6″-Chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development
[Image: see text] We previously reported the design of spirooxindoles with two identical substituents at the carbon-2 of the pyrrolidine core as potent MDM2 inhibitors. In this paper we describe an extensive structure–activity relationship study of this class of MDM2 inhibitors, which led to the dis...
| Autores principales: | , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
American Chemical
Society
2017
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| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394527/ https://www.ncbi.nlm.nih.gov/pubmed/28339198 http://dx.doi.org/10.1021/acs.jmedchem.6b01665 |
| _version_ | 1783229746997362688 |
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| author | Aguilar, Angelo Lu, Jianfeng Liu, Liu Du, Ding Bernard, Denzil McEachern, Donna Przybranowski, Sally Li, Xiaoqin Luo, Ruijuan Wen, Bo Sun, Duxin Wang, Hengbang Wen, Jianfeng Wang, Guangfeng Zhai, Yifan Guo, Ming Yang, Dajun Wang, Shaomeng |
| author_facet | Aguilar, Angelo Lu, Jianfeng Liu, Liu Du, Ding Bernard, Denzil McEachern, Donna Przybranowski, Sally Li, Xiaoqin Luo, Ruijuan Wen, Bo Sun, Duxin Wang, Hengbang Wen, Jianfeng Wang, Guangfeng Zhai, Yifan Guo, Ming Yang, Dajun Wang, Shaomeng |
| author_sort | Aguilar, Angelo |
| collection | PubMed |
| description | [Image: see text] We previously reported the design of spirooxindoles with two identical substituents at the carbon-2 of the pyrrolidine core as potent MDM2 inhibitors. In this paper we describe an extensive structure–activity relationship study of this class of MDM2 inhibitors, which led to the discovery of 60 (AA-115/APG-115). Compound 60 has a very high affinity to MDM2 (K(i) < 1 nM), potent cellular activity, and an excellent oral pharmacokinetic profile. Compound 60 is capable of achieving complete and long-lasting tumor regression in vivo and is currently in phase I clinical trials for cancer treatment. |
| format | Online Article Text |
| id | pubmed-5394527 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2017 |
| publisher | American Chemical
Society |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-53945272017-04-20 Discovery of 4-((3′R,4′S,5′R)-6″-Chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development Aguilar, Angelo Lu, Jianfeng Liu, Liu Du, Ding Bernard, Denzil McEachern, Donna Przybranowski, Sally Li, Xiaoqin Luo, Ruijuan Wen, Bo Sun, Duxin Wang, Hengbang Wen, Jianfeng Wang, Guangfeng Zhai, Yifan Guo, Ming Yang, Dajun Wang, Shaomeng J Med Chem [Image: see text] We previously reported the design of spirooxindoles with two identical substituents at the carbon-2 of the pyrrolidine core as potent MDM2 inhibitors. In this paper we describe an extensive structure–activity relationship study of this class of MDM2 inhibitors, which led to the discovery of 60 (AA-115/APG-115). Compound 60 has a very high affinity to MDM2 (K(i) < 1 nM), potent cellular activity, and an excellent oral pharmacokinetic profile. Compound 60 is capable of achieving complete and long-lasting tumor regression in vivo and is currently in phase I clinical trials for cancer treatment. American Chemical Society 2017-03-24 2017-04-13 /pmc/articles/PMC5394527/ /pubmed/28339198 http://dx.doi.org/10.1021/acs.jmedchem.6b01665 Text en Copyright © 2017 American Chemical Society This is an open access article published under an ACS AuthorChoice License (http://pubs.acs.org/page/policy/authorchoice_termsofuse.html) , which permits copying and redistribution of the article or any adaptations for non-commercial purposes. |
| spellingShingle | Aguilar, Angelo Lu, Jianfeng Liu, Liu Du, Ding Bernard, Denzil McEachern, Donna Przybranowski, Sally Li, Xiaoqin Luo, Ruijuan Wen, Bo Sun, Duxin Wang, Hengbang Wen, Jianfeng Wang, Guangfeng Zhai, Yifan Guo, Ming Yang, Dajun Wang, Shaomeng Discovery of 4-((3′R,4′S,5′R)-6″-Chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute 2 (MDM2) Inhibitor in Clinical Development |
| title | Discovery of 4-((3′R,4′S,5′R)-6″-Chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic
Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute
2 (MDM2) Inhibitor in Clinical Development |
| title_full | Discovery of 4-((3′R,4′S,5′R)-6″-Chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic
Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute
2 (MDM2) Inhibitor in Clinical Development |
| title_fullStr | Discovery of 4-((3′R,4′S,5′R)-6″-Chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic
Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute
2 (MDM2) Inhibitor in Clinical Development |
| title_full_unstemmed | Discovery of 4-((3′R,4′S,5′R)-6″-Chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic
Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute
2 (MDM2) Inhibitor in Clinical Development |
| title_short | Discovery of 4-((3′R,4′S,5′R)-6″-Chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic
Acid (AA-115/APG-115): A Potent and Orally Active Murine Double Minute
2 (MDM2) Inhibitor in Clinical Development |
| title_sort | discovery of 4-((3′r,4′s,5′r)-6″-chloro-4′-(3-chloro-2-fluorophenyl)-1′-ethyl-2″-oxodispiro[cyclohexane-1,2′-pyrrolidine-3′,3″-indoline]-5′-carboxamido)bicyclo[2.2.2]octane-1-carboxylic
acid (aa-115/apg-115): a potent and orally active murine double minute
2 (mdm2) inhibitor in clinical development |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5394527/ https://www.ncbi.nlm.nih.gov/pubmed/28339198 http://dx.doi.org/10.1021/acs.jmedchem.6b01665 |
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