Discovery of novel 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide derivatives as HIF prolyl 4-hydroxylase inhibitors; SAR, synthesis and modeling evaluation
The design, synthesis, and capacity to inhibit HIF prolyl 4-hydroxylases (PHDs) are described for 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide analogs. These analogs revealed two kinds of novel scaffolds as PHD2 inhibitors. Synthetic routes were developed for the preparation of their analog...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2014-07, Vol.24 (14), p.3142-3145 |
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| container_title | Bioorganic & medicinal chemistry letters |
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| creator | Hong, Yong Rae Kim, Hyun Tae Ro, Seonggu Cho, Joong Myung Lee, Sang Hwi Kim, In Su Jung, Young Hoon |
| description | The design, synthesis, and capacity to inhibit HIF prolyl 4-hydroxylases (PHDs) are described for 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide analogs. These analogs revealed two kinds of novel scaffolds as PHD2 inhibitors. Synthetic routes were developed for the preparation of their analogs containing the new scaffolds. In addition, the structure–activity relationship (SAR) of the 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide derivatives and their biological activities were reported. The complex structure of compound 18 with PHD2 was also obtained for the purpose of more efficient lead optimization. |
| doi_str_mv | 10.1016/j.bmcl.2014.05.003 |
| format | Article |
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These analogs revealed two kinds of novel scaffolds as PHD2 inhibitors. Synthetic routes were developed for the preparation of their analogs containing the new scaffolds. In addition, the structure–activity relationship (SAR) of the 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide derivatives and their biological activities were reported. 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The complex structure of compound 18 with PHD2 was also obtained for the purpose of more efficient lead optimization.</description><subject>Acetamides - chemical synthesis</subject><subject>Acetamides - chemistry</subject><subject>Acetamides - pharmacology</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Discovery</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - chemistry</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>EPO</subject><subject>HIF-PHs (PHDs)</subject><subject>Humans</subject><subject>Hypoxia-Inducible Factor-Proline Dioxygenases - antagonists & inhibitors</subject><subject>Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism</subject><subject>Inhibitor</subject><subject>Models, Molecular</subject><subject>Molecular Structure</subject><subject>Pyridines - chemical synthesis</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacology</subject><subject>Stabilizer</subject><subject>Structure-Activity Relationship</subject><subject>Thiazoles - chemical synthesis</subject><subject>Thiazoles - chemistry</subject><subject>Thiazoles - pharmacology</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNkV9rFDEUxYModq1-AR8kjy2YaZLJZGbQl9JaWygU_AOCSMgkd9wsmcmazA6OX8cvapZtfRSfbu7ldw7hHIReMlowyuTZpugG4wtOmShoVVBaPkIrJqQgpaDVY7SiraSkacWXI_QspQ3NIBXiKTriIl8rSVfo96VLJswQFxx6POaXx5x85eSkJOvFxvBzIdslOutGwsniT8m0dvpX8ETk7RvRBiY9OAvYQnSzntwMCeuEr2-u8DYGv3gsHpy8ToDduHadm0JMb_DH8w-vcVrGaQ3JZdlo8RAseDd-xzBrv8t-YXyOnvTaJ3hxP4_R56t3ny6uye3d-5uL81tiyqadCJO2bozkULetyaeamroDWgtraSl6DTm0DoSpwQhpKuBasqaVvOlF1_KyLY_RycE3__vHDtKkhhwOeK9HCLukWCUEpTVv5H-gpZSNKDnLKD-gJoaUIvRqG92g46IYVfse1Ubte1T7HhWtVO4xi17d---6AexfyUNxGXh7ACAHMjuIKhkHowHrIphJ2eD-5f8Hw22viQ</recordid><startdate>20140715</startdate><enddate>20140715</enddate><creator>Hong, Yong Rae</creator><creator>Kim, Hyun Tae</creator><creator>Ro, Seonggu</creator><creator>Cho, Joong Myung</creator><creator>Lee, Sang Hwi</creator><creator>Kim, In Su</creator><creator>Jung, Young Hoon</creator><general>Elsevier Ltd</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><scope>7QO</scope><scope>8FD</scope><scope>FR3</scope><scope>P64</scope></search><sort><creationdate>20140715</creationdate><title>Discovery of novel 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide derivatives as HIF prolyl 4-hydroxylase inhibitors; SAR, synthesis and modeling evaluation</title><author>Hong, Yong Rae ; Kim, Hyun Tae ; Ro, Seonggu ; Cho, Joong Myung ; Lee, Sang Hwi ; Kim, In Su ; Jung, Young Hoon</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c389t-16d78c62e799cc3870c7be074dd034fae101be4c7ec46c5e2a6189628f4b92393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Acetamides - chemical synthesis</topic><topic>Acetamides - chemistry</topic><topic>Acetamides - pharmacology</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Discovery</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - chemistry</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>EPO</topic><topic>HIF-PHs (PHDs)</topic><topic>Humans</topic><topic>Hypoxia-Inducible Factor-Proline Dioxygenases - antagonists & inhibitors</topic><topic>Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism</topic><topic>Inhibitor</topic><topic>Models, Molecular</topic><topic>Molecular Structure</topic><topic>Pyridines - chemical synthesis</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - pharmacology</topic><topic>Stabilizer</topic><topic>Structure-Activity Relationship</topic><topic>Thiazoles - chemical synthesis</topic><topic>Thiazoles - chemistry</topic><topic>Thiazoles - pharmacology</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Hong, Yong Rae</creatorcontrib><creatorcontrib>Kim, Hyun Tae</creatorcontrib><creatorcontrib>Ro, Seonggu</creatorcontrib><creatorcontrib>Cho, Joong Myung</creatorcontrib><creatorcontrib>Lee, Sang Hwi</creatorcontrib><creatorcontrib>Kim, In Su</creatorcontrib><creatorcontrib>Jung, Young Hoon</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><collection>Biotechnology Research Abstracts</collection><collection>Technology Research Database</collection><collection>Engineering Research Database</collection><collection>Biotechnology and BioEngineering Abstracts</collection><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Hong, Yong Rae</au><au>Kim, Hyun Tae</au><au>Ro, Seonggu</au><au>Cho, Joong Myung</au><au>Lee, Sang Hwi</au><au>Kim, In Su</au><au>Jung, Young Hoon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of novel 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide derivatives as HIF prolyl 4-hydroxylase inhibitors; SAR, synthesis and modeling evaluation</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2014-07-15</date><risdate>2014</risdate><volume>24</volume><issue>14</issue><spage>3142</spage><epage>3145</epage><pages>3142-3145</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>The design, synthesis, and capacity to inhibit HIF prolyl 4-hydroxylases (PHDs) are described for 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide analogs. 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| subjects | Acetamides - chemical synthesis Acetamides - chemistry Acetamides - pharmacology Dose-Response Relationship, Drug Drug Discovery Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - chemistry Enzyme Inhibitors - pharmacology EPO HIF-PHs (PHDs) Humans Hypoxia-Inducible Factor-Proline Dioxygenases - antagonists & inhibitors Hypoxia-Inducible Factor-Proline Dioxygenases - metabolism Inhibitor Models, Molecular Molecular Structure Pyridines - chemical synthesis Pyridines - chemistry Pyridines - pharmacology Stabilizer Structure-Activity Relationship Thiazoles - chemical synthesis Thiazoles - chemistry Thiazoles - pharmacology |
| title | Discovery of novel 2-[2-(3-hydroxy-pyridin-2-yl)-thiazol-4-yl]-acetamide derivatives as HIF prolyl 4-hydroxylase inhibitors; SAR, synthesis and modeling evaluation |
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