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Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes
[Image: see text] The imidazolyl-tetrahydro-β-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, tel...
| Autores principales: | , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , |
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| Formato: | Online Artículo Texto |
| Lenguaje: | English |
| Publicado: |
American Chemical
Society
2015
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| Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4434471/ https://www.ncbi.nlm.nih.gov/pubmed/26005524 http://dx.doi.org/10.1021/ml500514w |
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| author | Shah, Shrenik K. He, Shuwen Guo, Liangqin Truong, Quang Qi, Hongbo Du, Wu Lai, Zhong Liu, Jian Jian, Tianying Hong, Qingmei Dobbelaar, Peter Ye, Zhixiong Sherer, Edward Feng, Zhe Yu, Yang Wong, Frederick Samuel, Koppara Madiera, Maria Karanam, Bindhu V. Reddy, Vijay B. Mitelman, Stan Tong, Sharon X. Chicchi, Gary G. Tsao, Kwei-Lan Trusca, Dorina Feng, Yue Wu, Margaret Shao, Qing Trujillo, Maria E. Eiermann, George J. Li, Cai Pachanski, Michele Fernandez, Guillermo Nelson, Donald Bunting, Patricia Morissette, Pierre Volksdorf, Sylvia Kerr, Janet Zhang, Bei B. Howard, Andrew D. Zhou, Yun-Ping Pasternak, Alexander Nargund, Ravi P. Hagmann, William K. |
| author_facet | Shah, Shrenik K. He, Shuwen Guo, Liangqin Truong, Quang Qi, Hongbo Du, Wu Lai, Zhong Liu, Jian Jian, Tianying Hong, Qingmei Dobbelaar, Peter Ye, Zhixiong Sherer, Edward Feng, Zhe Yu, Yang Wong, Frederick Samuel, Koppara Madiera, Maria Karanam, Bindhu V. Reddy, Vijay B. Mitelman, Stan Tong, Sharon X. Chicchi, Gary G. Tsao, Kwei-Lan Trusca, Dorina Feng, Yue Wu, Margaret Shao, Qing Trujillo, Maria E. Eiermann, George J. Li, Cai Pachanski, Michele Fernandez, Guillermo Nelson, Donald Bunting, Patricia Morissette, Pierre Volksdorf, Sylvia Kerr, Janet Zhang, Bei B. Howard, Andrew D. Zhou, Yun-Ping Pasternak, Alexander Nargund, Ravi P. Hagmann, William K. |
| author_sort | Shah, Shrenik K. |
| collection | PubMed |
| description | [Image: see text] The imidazolyl-tetrahydro-β-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline (17e, MK-1421). |
| format | Online Article Text |
| id | pubmed-4434471 |
| institution | National Center for Biotechnology Information |
| language | English |
| publishDate | 2015 |
| publisher | American Chemical
Society |
| record_format | MEDLINE/PubMed |
| spelling | pubmed-44344712016-05-14 Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes Shah, Shrenik K. He, Shuwen Guo, Liangqin Truong, Quang Qi, Hongbo Du, Wu Lai, Zhong Liu, Jian Jian, Tianying Hong, Qingmei Dobbelaar, Peter Ye, Zhixiong Sherer, Edward Feng, Zhe Yu, Yang Wong, Frederick Samuel, Koppara Madiera, Maria Karanam, Bindhu V. Reddy, Vijay B. Mitelman, Stan Tong, Sharon X. Chicchi, Gary G. Tsao, Kwei-Lan Trusca, Dorina Feng, Yue Wu, Margaret Shao, Qing Trujillo, Maria E. Eiermann, George J. Li, Cai Pachanski, Michele Fernandez, Guillermo Nelson, Donald Bunting, Patricia Morissette, Pierre Volksdorf, Sylvia Kerr, Janet Zhang, Bei B. Howard, Andrew D. Zhou, Yun-Ping Pasternak, Alexander Nargund, Ravi P. Hagmann, William K. ACS Med Chem Lett [Image: see text] The imidazolyl-tetrahydro-β-carboline class of sstr3 antagonists have demonstrated efficacy in a murine model of glucose excursion and may have potential as a treatment for type 2 diabetes. The first candidate in this class caused unacceptable QTc interval prolongation in oral, telemetrized cardiovascular (CV) dogs. Herein, we describe our efforts to identify an acceptable candidate without CV effects. These efforts resulted in the identification of (1R,3R)-3-(4-(5-fluoropyridin-2-yl)-1H-imidazol-2-yl)-1-(1-ethyl-pyrazol-4-yl)-1-(3-methyl-1,3,4-oxadiazol-3H-2-one-5-yl)-2,3,4,9-tetrahydro-1H-β-carboline (17e, MK-1421). American Chemical Society 2015-03-18 /pmc/articles/PMC4434471/ /pubmed/26005524 http://dx.doi.org/10.1021/ml500514w Text en Copyright © 2015 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 | Shah, Shrenik K. He, Shuwen Guo, Liangqin Truong, Quang Qi, Hongbo Du, Wu Lai, Zhong Liu, Jian Jian, Tianying Hong, Qingmei Dobbelaar, Peter Ye, Zhixiong Sherer, Edward Feng, Zhe Yu, Yang Wong, Frederick Samuel, Koppara Madiera, Maria Karanam, Bindhu V. Reddy, Vijay B. Mitelman, Stan Tong, Sharon X. Chicchi, Gary G. Tsao, Kwei-Lan Trusca, Dorina Feng, Yue Wu, Margaret Shao, Qing Trujillo, Maria E. Eiermann, George J. Li, Cai Pachanski, Michele Fernandez, Guillermo Nelson, Donald Bunting, Patricia Morissette, Pierre Volksdorf, Sylvia Kerr, Janet Zhang, Bei B. Howard, Andrew D. Zhou, Yun-Ping Pasternak, Alexander Nargund, Ravi P. Hagmann, William K. Discovery of MK-1421, a Potent, Selective sstr3 Antagonist, as a Development Candidate for Type 2 Diabetes |
| title | Discovery of MK-1421, a Potent, Selective sstr3 Antagonist,
as a Development Candidate for Type 2 Diabetes |
| title_full | Discovery of MK-1421, a Potent, Selective sstr3 Antagonist,
as a Development Candidate for Type 2 Diabetes |
| title_fullStr | Discovery of MK-1421, a Potent, Selective sstr3 Antagonist,
as a Development Candidate for Type 2 Diabetes |
| title_full_unstemmed | Discovery of MK-1421, a Potent, Selective sstr3 Antagonist,
as a Development Candidate for Type 2 Diabetes |
| title_short | Discovery of MK-1421, a Potent, Selective sstr3 Antagonist,
as a Development Candidate for Type 2 Diabetes |
| title_sort | discovery of mk-1421, a potent, selective sstr3 antagonist,
as a development candidate for type 2 diabetes |
| url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4434471/ https://www.ncbi.nlm.nih.gov/pubmed/26005524 http://dx.doi.org/10.1021/ml500514w |
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