Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control
The design of a new series of agonists of the orphan G-protein coupled receptor GPR119, starting from AR231453 is outlined. This resulted in the discovery of 3k (APD668, JNJ-28630368), the first compound with this mechanism of action to be progressed into clinical development for the treatment of di...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2011-05, Vol.21 (10), p.3134-3141 |
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| creator | Semple, Graeme Ren, Albert Fioravanti, Beatriz Pereira, Guillherme Calderon, Imelda Choi, Karoline Xiong, Yifeng Shin, Young-Jun Gharbaoui, Tawfik Sage, Carleton R. Morgan, Michael Xing, Charles Chu, Zhi-Liang Leonard, James N. Grottick, Andrew J. Al-Shamma, Hussein Liang, Yin Demarest, Keith T. Jones, Robert M. |
| description | The design of a new series of agonists of the orphan G-protein coupled receptor GPR119, starting from
AR231453 is outlined. This resulted in the discovery of
3k (APD668, JNJ-28630368), the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes.
We herein outline the design of a new series of agonists of the pancreatic and GI-expressed orphan G-protein coupled receptor GPR119, a target that has been of significant recent interest in the field of metabolism, starting from our prototypical agonist
AR231453. A number of key parameters were improved first by incorporation of a pyrazolopyrimidine core to create a new structural series and secondly by the introduction of a piperidine ether group capped with a carbamate. Chronic treatment with one compound from the series,
3k, showed for the first time that blood glucose and glycated hemoglobin (HbA1c) levels could be significantly reduced in Zucker Diabetic Fatty (ZDF) rats over several weeks of dosing. As a result of these and other data described here,
3k (APD668, JNJ-28630368) was the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes. |
| doi_str_mv | 10.1016/j.bmcl.2011.03.007 |
| format | Article |
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AR231453 is outlined. This resulted in the discovery of
3k (APD668, JNJ-28630368), the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes.
We herein outline the design of a new series of agonists of the pancreatic and GI-expressed orphan G-protein coupled receptor GPR119, a target that has been of significant recent interest in the field of metabolism, starting from our prototypical agonist
AR231453. A number of key parameters were improved first by incorporation of a pyrazolopyrimidine core to create a new structural series and secondly by the introduction of a piperidine ether group capped with a carbamate. Chronic treatment with one compound from the series,
3k, showed for the first time that blood glucose and glycated hemoglobin (HbA1c) levels could be significantly reduced in Zucker Diabetic Fatty (ZDF) rats over several weeks of dosing. As a result of these and other data described here,
3k (APD668, JNJ-28630368) was the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2011.03.007</identifier><identifier>PMID: 21444206</identifier><language>eng</language><publisher>Amsterdam: Elsevier Ltd</publisher><subject>agonists ; animal models ; Animals ; Biological and medical sciences ; Blood ; blood glucose ; Blood Glucose - drug effects ; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis ; Bridged Bicyclo Compounds, Heterocyclic - chemistry ; Bridged Bicyclo Compounds, Heterocyclic - pharmacology ; Data processing ; Diabetes ; Diabetes mellitus ; Disease Models, Animal ; double prime G protein-coupled receptors ; Drug Discovery ; Ethers ; G-protein coupled receptors ; GDIS ; General and cellular metabolism. Vitamins ; Glucose ; Glucose - metabolism ; glycemic control ; glycohemoglobin ; GPCR ; GPR119 agonists ; Hemoglobin ; Hypoglycemic Agents - chemical synthesis ; Hypoglycemic Agents - chemistry ; Hypoglycemic Agents - pharmacology ; mechanism of action ; Medical sciences ; Metabolism ; Molecular Structure ; Oxadiazoles - chemistry ; Oxadiazoles - pharmacology ; Pancreas ; Pharmacology. Drug treatments ; Piperidine ; piperidines ; Pyrazoles - chemistry ; Pyrazoles - pharmacology ; pyrazolopyrimidines ; Pyrimidines - chemistry ; Pyrimidines - pharmacology ; Rats ; Rats, Zucker ; Receptors, G-Protein-Coupled - agonists</subject><ispartof>Bioorganic & medicinal chemistry letters, 2011-05, Vol.21 (10), p.3134-3141</ispartof><rights>2011 Elsevier Ltd</rights><rights>2015 INIST-CNRS</rights><rights>Copyright © 2011 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c441t-954a99f1a2f569779af2d8e3284baa1a02b72947bbb28fc7c280ad41c61f9a793</citedby><cites>FETCH-LOGICAL-c441t-954a99f1a2f569779af2d8e3284baa1a02b72947bbb28fc7c280ad41c61f9a793</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X11003180$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=24163001$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/21444206$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Semple, Graeme</creatorcontrib><creatorcontrib>Ren, Albert</creatorcontrib><creatorcontrib>Fioravanti, Beatriz</creatorcontrib><creatorcontrib>Pereira, Guillherme</creatorcontrib><creatorcontrib>Calderon, Imelda</creatorcontrib><creatorcontrib>Choi, Karoline</creatorcontrib><creatorcontrib>Xiong, Yifeng</creatorcontrib><creatorcontrib>Shin, Young-Jun</creatorcontrib><creatorcontrib>Gharbaoui, Tawfik</creatorcontrib><creatorcontrib>Sage, Carleton R.</creatorcontrib><creatorcontrib>Morgan, Michael</creatorcontrib><creatorcontrib>Xing, Charles</creatorcontrib><creatorcontrib>Chu, Zhi-Liang</creatorcontrib><creatorcontrib>Leonard, James N.</creatorcontrib><creatorcontrib>Grottick, Andrew J.</creatorcontrib><creatorcontrib>Al-Shamma, Hussein</creatorcontrib><creatorcontrib>Liang, Yin</creatorcontrib><creatorcontrib>Demarest, Keith T.</creatorcontrib><creatorcontrib>Jones, Robert M.</creatorcontrib><title>Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>The design of a new series of agonists of the orphan G-protein coupled receptor GPR119, starting from
AR231453 is outlined. This resulted in the discovery of
3k (APD668, JNJ-28630368), the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes.
We herein outline the design of a new series of agonists of the pancreatic and GI-expressed orphan G-protein coupled receptor GPR119, a target that has been of significant recent interest in the field of metabolism, starting from our prototypical agonist
AR231453. A number of key parameters were improved first by incorporation of a pyrazolopyrimidine core to create a new structural series and secondly by the introduction of a piperidine ether group capped with a carbamate. Chronic treatment with one compound from the series,
3k, showed for the first time that blood glucose and glycated hemoglobin (HbA1c) levels could be significantly reduced in Zucker Diabetic Fatty (ZDF) rats over several weeks of dosing. As a result of these and other data described here,
3k (APD668, JNJ-28630368) was the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes.</description><subject>agonists</subject><subject>animal models</subject><subject>Animals</subject><subject>Biological and medical sciences</subject><subject>Blood</subject><subject>blood glucose</subject><subject>Blood Glucose - drug effects</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - chemistry</subject><subject>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</subject><subject>Data processing</subject><subject>Diabetes</subject><subject>Diabetes mellitus</subject><subject>Disease Models, Animal</subject><subject>double prime G protein-coupled receptors</subject><subject>Drug Discovery</subject><subject>Ethers</subject><subject>G-protein coupled receptors</subject><subject>GDIS</subject><subject>General and cellular metabolism. Vitamins</subject><subject>Glucose</subject><subject>Glucose - metabolism</subject><subject>glycemic control</subject><subject>glycohemoglobin</subject><subject>GPCR</subject><subject>GPR119 agonists</subject><subject>Hemoglobin</subject><subject>Hypoglycemic Agents - chemical synthesis</subject><subject>Hypoglycemic Agents - chemistry</subject><subject>Hypoglycemic Agents - pharmacology</subject><subject>mechanism of action</subject><subject>Medical sciences</subject><subject>Metabolism</subject><subject>Molecular Structure</subject><subject>Oxadiazoles - chemistry</subject><subject>Oxadiazoles - pharmacology</subject><subject>Pancreas</subject><subject>Pharmacology. Drug treatments</subject><subject>Piperidine</subject><subject>piperidines</subject><subject>Pyrazoles - chemistry</subject><subject>Pyrazoles - pharmacology</subject><subject>pyrazolopyrimidines</subject><subject>Pyrimidines - chemistry</subject><subject>Pyrimidines - pharmacology</subject><subject>Rats</subject><subject>Rats, Zucker</subject><subject>Receptors, G-Protein-Coupled - agonists</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2011</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFkUGP1CAUx4nRuLOrX8CDcjF7agX6pi2JF7PqaLKJRt3EG6EUZpjQMgKtmS_hZ5Y6o9709BLe7_2B90PoCSUlJbR-sS-7QbmSEUpLUpWENPfQikINRQVkfR-tCK9J0XL4eoEuY9wTQoEAPEQXjAIAI_UK_Xhto_KzDkfsDTZT1D3urDoqZxWWWz_amOLSSjuNfTjs5Ig3xSH4pO2IlZ8OLk8ErfQh-YA3Hz9RyvF3m3Y492c7eyxVsrNNx-Ug-F6PCQ-5uF-xWzcpH3VOGlPw7hF6YKSL-vG5XqG7t2--3Lwrbj9s3t-8ui0UAE0FX4Pk3FDJzLrmTcOlYX2rK9ZCJyWVhHUN49B0XcdaoxrFWiJ7oKqmhsuGV1fo-pSbf_Jt0jGJIe9BOydH7aco2gYobyrC_k_WkO-vaZtJdiJV8DEGbcQh2EGGo6BELMLEXizCxCJMkEpkYXno6Tl-6gbd_xn5bSgDz8-AjEo6E-SobPzLAa2rLDZzz06ckV7IbcjM3ed803ppQkshEy9PRF69nq0OIiqrR6V7m_0l0Xv7r5f-BPmrvi0</recordid><startdate>20110515</startdate><enddate>20110515</enddate><creator>Semple, Graeme</creator><creator>Ren, Albert</creator><creator>Fioravanti, Beatriz</creator><creator>Pereira, Guillherme</creator><creator>Calderon, Imelda</creator><creator>Choi, Karoline</creator><creator>Xiong, Yifeng</creator><creator>Shin, Young-Jun</creator><creator>Gharbaoui, Tawfik</creator><creator>Sage, Carleton R.</creator><creator>Morgan, Michael</creator><creator>Xing, Charles</creator><creator>Chu, Zhi-Liang</creator><creator>Leonard, James N.</creator><creator>Grottick, Andrew J.</creator><creator>Al-Shamma, Hussein</creator><creator>Liang, Yin</creator><creator>Demarest, Keith T.</creator><creator>Jones, Robert M.</creator><general>Elsevier Ltd</general><general>Elsevier</general><scope>FBQ</scope><scope>IQODW</scope><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>20110515</creationdate><title>Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control</title><author>Semple, Graeme ; Ren, Albert ; Fioravanti, Beatriz ; Pereira, Guillherme ; Calderon, Imelda ; Choi, Karoline ; Xiong, Yifeng ; Shin, Young-Jun ; Gharbaoui, Tawfik ; Sage, Carleton R. ; Morgan, Michael ; Xing, Charles ; Chu, Zhi-Liang ; Leonard, James N. ; Grottick, Andrew J. ; Al-Shamma, Hussein ; Liang, Yin ; Demarest, Keith T. ; Jones, Robert M.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c441t-954a99f1a2f569779af2d8e3284baa1a02b72947bbb28fc7c280ad41c61f9a793</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2011</creationdate><topic>agonists</topic><topic>animal models</topic><topic>Animals</topic><topic>Biological and medical sciences</topic><topic>Blood</topic><topic>blood glucose</topic><topic>Blood Glucose - drug effects</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - chemistry</topic><topic>Bridged Bicyclo Compounds, Heterocyclic - pharmacology</topic><topic>Data processing</topic><topic>Diabetes</topic><topic>Diabetes mellitus</topic><topic>Disease Models, Animal</topic><topic>double prime G protein-coupled receptors</topic><topic>Drug Discovery</topic><topic>Ethers</topic><topic>G-protein coupled receptors</topic><topic>GDIS</topic><topic>General and cellular metabolism. Vitamins</topic><topic>Glucose</topic><topic>Glucose - metabolism</topic><topic>glycemic control</topic><topic>glycohemoglobin</topic><topic>GPCR</topic><topic>GPR119 agonists</topic><topic>Hemoglobin</topic><topic>Hypoglycemic Agents - chemical synthesis</topic><topic>Hypoglycemic Agents - chemistry</topic><topic>Hypoglycemic Agents - pharmacology</topic><topic>mechanism of action</topic><topic>Medical sciences</topic><topic>Metabolism</topic><topic>Molecular Structure</topic><topic>Oxadiazoles - chemistry</topic><topic>Oxadiazoles - pharmacology</topic><topic>Pancreas</topic><topic>Pharmacology. Drug treatments</topic><topic>Piperidine</topic><topic>piperidines</topic><topic>Pyrazoles - chemistry</topic><topic>Pyrazoles - pharmacology</topic><topic>pyrazolopyrimidines</topic><topic>Pyrimidines - chemistry</topic><topic>Pyrimidines - pharmacology</topic><topic>Rats</topic><topic>Rats, Zucker</topic><topic>Receptors, G-Protein-Coupled - agonists</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Semple, Graeme</creatorcontrib><creatorcontrib>Ren, Albert</creatorcontrib><creatorcontrib>Fioravanti, Beatriz</creatorcontrib><creatorcontrib>Pereira, Guillherme</creatorcontrib><creatorcontrib>Calderon, Imelda</creatorcontrib><creatorcontrib>Choi, Karoline</creatorcontrib><creatorcontrib>Xiong, Yifeng</creatorcontrib><creatorcontrib>Shin, Young-Jun</creatorcontrib><creatorcontrib>Gharbaoui, Tawfik</creatorcontrib><creatorcontrib>Sage, Carleton R.</creatorcontrib><creatorcontrib>Morgan, Michael</creatorcontrib><creatorcontrib>Xing, Charles</creatorcontrib><creatorcontrib>Chu, Zhi-Liang</creatorcontrib><creatorcontrib>Leonard, James N.</creatorcontrib><creatorcontrib>Grottick, Andrew J.</creatorcontrib><creatorcontrib>Al-Shamma, Hussein</creatorcontrib><creatorcontrib>Liang, Yin</creatorcontrib><creatorcontrib>Demarest, Keith T.</creatorcontrib><creatorcontrib>Jones, Robert M.</creatorcontrib><collection>AGRIS</collection><collection>Pascal-Francis</collection><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>Semple, Graeme</au><au>Ren, Albert</au><au>Fioravanti, Beatriz</au><au>Pereira, Guillherme</au><au>Calderon, Imelda</au><au>Choi, Karoline</au><au>Xiong, Yifeng</au><au>Shin, Young-Jun</au><au>Gharbaoui, Tawfik</au><au>Sage, Carleton R.</au><au>Morgan, Michael</au><au>Xing, Charles</au><au>Chu, Zhi-Liang</au><au>Leonard, James N.</au><au>Grottick, Andrew J.</au><au>Al-Shamma, Hussein</au><au>Liang, Yin</au><au>Demarest, Keith T.</au><au>Jones, Robert M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2011-05-15</date><risdate>2011</risdate><volume>21</volume><issue>10</issue><spage>3134</spage><epage>3141</epage><pages>3134-3141</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>The design of a new series of agonists of the orphan G-protein coupled receptor GPR119, starting from
AR231453 is outlined. This resulted in the discovery of
3k (APD668, JNJ-28630368), the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes.
We herein outline the design of a new series of agonists of the pancreatic and GI-expressed orphan G-protein coupled receptor GPR119, a target that has been of significant recent interest in the field of metabolism, starting from our prototypical agonist
AR231453. A number of key parameters were improved first by incorporation of a pyrazolopyrimidine core to create a new structural series and secondly by the introduction of a piperidine ether group capped with a carbamate. Chronic treatment with one compound from the series,
3k, showed for the first time that blood glucose and glycated hemoglobin (HbA1c) levels could be significantly reduced in Zucker Diabetic Fatty (ZDF) rats over several weeks of dosing. As a result of these and other data described here,
3k (APD668, JNJ-28630368) was the first compound with this mechanism of action to be progressed into clinical development for the treatment of diabetes.</abstract><cop>Amsterdam</cop><pub>Elsevier Ltd</pub><pmid>21444206</pmid><doi>10.1016/j.bmcl.2011.03.007</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2011-05, Vol.21 (10), p.3134-3141 |
| issn | 0960-894X 1464-3405 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_874197302 |
| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | agonists animal models Animals Biological and medical sciences Blood blood glucose Blood Glucose - drug effects Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis Bridged Bicyclo Compounds, Heterocyclic - chemistry Bridged Bicyclo Compounds, Heterocyclic - pharmacology Data processing Diabetes Diabetes mellitus Disease Models, Animal double prime G protein-coupled receptors Drug Discovery Ethers G-protein coupled receptors GDIS General and cellular metabolism. Vitamins Glucose Glucose - metabolism glycemic control glycohemoglobin GPCR GPR119 agonists Hemoglobin Hypoglycemic Agents - chemical synthesis Hypoglycemic Agents - chemistry Hypoglycemic Agents - pharmacology mechanism of action Medical sciences Metabolism Molecular Structure Oxadiazoles - chemistry Oxadiazoles - pharmacology Pancreas Pharmacology. Drug treatments Piperidine piperidines Pyrazoles - chemistry Pyrazoles - pharmacology pyrazolopyrimidines Pyrimidines - chemistry Pyrimidines - pharmacology Rats Rats, Zucker Receptors, G-Protein-Coupled - agonists |
| title | Discovery of fused bicyclic agonists of the orphan G-protein coupled receptor GPR119 with in vivo activity in rodent models of glucose control |
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