Identification of potent, nonabsorbable agonists of the calcium-sensing receptor for GI-specific administration
[Display omitted] Modulation of gastrointestinal nutrient sensing pathways provides a promising a new approach for the treatment of metabolic diseases including diabetes and obesity. The calcium-sensing receptor has been identified as a key receptor involved in mineral and amino acid nutrient sensin...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2017-10, Vol.27 (20), p.4673-4677 |
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| container_end_page | 4677 |
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| container_issue | 20 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 27 |
| creator | Sparks, Steven M. Spearing, Paul K. Diaz, Caroline J. Cowan, David J. Jayawickreme, Channa Chen, Grace Rimele, Thomas J. Generaux, Claudia Harston, Lindsey T. Roller, Shane G. |
| description | [Display omitted]
Modulation of gastrointestinal nutrient sensing pathways provides a promising a new approach for the treatment of metabolic diseases including diabetes and obesity. The calcium-sensing receptor has been identified as a key receptor involved in mineral and amino acid nutrient sensing and thus is an attractive target for modulation in the intestine. Herein we describe the optimization of gastrointestinally restricted calcium-sensing receptor agonists starting from a 3-aminopyrrolidine-containing template leading to the identification of GI-restricted agonist 19 (GSK3004774). |
| doi_str_mv | 10.1016/j.bmcl.2017.09.008 |
| format | Article |
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Modulation of gastrointestinal nutrient sensing pathways provides a promising a new approach for the treatment of metabolic diseases including diabetes and obesity. The calcium-sensing receptor has been identified as a key receptor involved in mineral and amino acid nutrient sensing and thus is an attractive target for modulation in the intestine. Herein we describe the optimization of gastrointestinally restricted calcium-sensing receptor agonists starting from a 3-aminopyrrolidine-containing template leading to the identification of GI-restricted agonist 19 (GSK3004774).</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2017.09.008</identifier><identifier>PMID: 28916340</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Calcium - metabolism ; Calcium sensing receptor ; Cell Membrane Permeability - drug effects ; Dogs ; Gastrointestinal Tract - metabolism ; GI-restricted ; HEK293 Cells ; Humans ; Madin Darby Canine Kidney Cells ; Nutrient sensing ; Pyrrolidines - chemistry ; Pyrrolidines - metabolism ; Pyrrolidines - pharmacology ; Receptors, Calcium-Sensing - agonists ; Receptors, Calcium-Sensing - genetics ; Receptors, Calcium-Sensing - metabolism ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2017-10, Vol.27 (20), p.4673-4677</ispartof><rights>2017 Elsevier Ltd</rights><rights>Copyright © 2017 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c356t-33a75aca510e07f6be3b81e4971d80f0ee4e7963d737118e2ca0e93bfa4aa2413</citedby><cites>FETCH-LOGICAL-c356t-33a75aca510e07f6be3b81e4971d80f0ee4e7963d737118e2ca0e93bfa4aa2413</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X1730896X$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/28916340$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sparks, Steven M.</creatorcontrib><creatorcontrib>Spearing, Paul K.</creatorcontrib><creatorcontrib>Diaz, Caroline J.</creatorcontrib><creatorcontrib>Cowan, David J.</creatorcontrib><creatorcontrib>Jayawickreme, Channa</creatorcontrib><creatorcontrib>Chen, Grace</creatorcontrib><creatorcontrib>Rimele, Thomas J.</creatorcontrib><creatorcontrib>Generaux, Claudia</creatorcontrib><creatorcontrib>Harston, Lindsey T.</creatorcontrib><creatorcontrib>Roller, Shane G.</creatorcontrib><title>Identification of potent, nonabsorbable agonists of the calcium-sensing receptor for GI-specific administration</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Modulation of gastrointestinal nutrient sensing pathways provides a promising a new approach for the treatment of metabolic diseases including diabetes and obesity. The calcium-sensing receptor has been identified as a key receptor involved in mineral and amino acid nutrient sensing and thus is an attractive target for modulation in the intestine. Herein we describe the optimization of gastrointestinally restricted calcium-sensing receptor agonists starting from a 3-aminopyrrolidine-containing template leading to the identification of GI-restricted agonist 19 (GSK3004774).</description><subject>Animals</subject><subject>Calcium - metabolism</subject><subject>Calcium sensing receptor</subject><subject>Cell Membrane Permeability - drug effects</subject><subject>Dogs</subject><subject>Gastrointestinal Tract - metabolism</subject><subject>GI-restricted</subject><subject>HEK293 Cells</subject><subject>Humans</subject><subject>Madin Darby Canine Kidney Cells</subject><subject>Nutrient sensing</subject><subject>Pyrrolidines - chemistry</subject><subject>Pyrrolidines - metabolism</subject><subject>Pyrrolidines - pharmacology</subject><subject>Receptors, Calcium-Sensing - agonists</subject><subject>Receptors, Calcium-Sensing - genetics</subject><subject>Receptors, Calcium-Sensing - metabolism</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2017</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kE1L5TAUhoOM6B31D7gYupyFrSdN-hFwI-LcuSC4UXAX0vRUc2mTTpIr-O9NvepyFuFAeN73cB5CzikUFGh9uS26SY9FCbQpQBQA7QFZUV7znHGofpAViBryVvCnY_IzhC0A5cD5ETkuW0HrBK2I2_RooxmMVtE4m7khm11MXxeZdVZ1wflOdSNm6tlZE2JYiPiCmVajNrspD2iDsc-ZR41zdD4b0ltv8jCjXmoz1U9mSfqPBafkcFBjwLPPeUIe_9w-3PzN7-7Xm5vru1yzqo45Y6qplFYVBYRmqDtkXUuRi4b2LQyAyLERNesb1lDaYqkVoGDdoLhSJafshPze987e_dthiHIyQeM4KotuFyQVHKCqaVsltNyj2rsQPA5y9mZS_k1SkItouZWLaLmIliBkEp1Cvz77d92E_Xfky2wCrvYApitfDXoZtEGrsTdJVZS9M__rfwcxKZEU</recordid><startdate>20171015</startdate><enddate>20171015</enddate><creator>Sparks, Steven M.</creator><creator>Spearing, Paul K.</creator><creator>Diaz, Caroline J.</creator><creator>Cowan, David J.</creator><creator>Jayawickreme, Channa</creator><creator>Chen, Grace</creator><creator>Rimele, Thomas J.</creator><creator>Generaux, Claudia</creator><creator>Harston, Lindsey T.</creator><creator>Roller, Shane G.</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></search><sort><creationdate>20171015</creationdate><title>Identification of potent, nonabsorbable agonists of the calcium-sensing receptor for GI-specific administration</title><author>Sparks, Steven M. ; Spearing, Paul K. ; Diaz, Caroline J. ; Cowan, David J. ; Jayawickreme, Channa ; Chen, Grace ; Rimele, Thomas J. ; Generaux, Claudia ; Harston, Lindsey T. ; Roller, Shane G.</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c356t-33a75aca510e07f6be3b81e4971d80f0ee4e7963d737118e2ca0e93bfa4aa2413</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2017</creationdate><topic>Animals</topic><topic>Calcium - metabolism</topic><topic>Calcium sensing receptor</topic><topic>Cell Membrane Permeability - drug effects</topic><topic>Dogs</topic><topic>Gastrointestinal Tract - metabolism</topic><topic>GI-restricted</topic><topic>HEK293 Cells</topic><topic>Humans</topic><topic>Madin Darby Canine Kidney Cells</topic><topic>Nutrient sensing</topic><topic>Pyrrolidines - chemistry</topic><topic>Pyrrolidines - metabolism</topic><topic>Pyrrolidines - pharmacology</topic><topic>Receptors, Calcium-Sensing - agonists</topic><topic>Receptors, Calcium-Sensing - genetics</topic><topic>Receptors, Calcium-Sensing - metabolism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sparks, Steven M.</creatorcontrib><creatorcontrib>Spearing, Paul K.</creatorcontrib><creatorcontrib>Diaz, Caroline J.</creatorcontrib><creatorcontrib>Cowan, David J.</creatorcontrib><creatorcontrib>Jayawickreme, Channa</creatorcontrib><creatorcontrib>Chen, Grace</creatorcontrib><creatorcontrib>Rimele, Thomas J.</creatorcontrib><creatorcontrib>Generaux, Claudia</creatorcontrib><creatorcontrib>Harston, Lindsey T.</creatorcontrib><creatorcontrib>Roller, Shane G.</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><jtitle>Bioorganic & medicinal chemistry letters</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Sparks, Steven M.</au><au>Spearing, Paul K.</au><au>Diaz, Caroline J.</au><au>Cowan, David J.</au><au>Jayawickreme, Channa</au><au>Chen, Grace</au><au>Rimele, Thomas J.</au><au>Generaux, Claudia</au><au>Harston, Lindsey T.</au><au>Roller, Shane G.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Identification of potent, nonabsorbable agonists of the calcium-sensing receptor for GI-specific administration</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2017-10-15</date><risdate>2017</risdate><volume>27</volume><issue>20</issue><spage>4673</spage><epage>4677</epage><pages>4673-4677</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
Modulation of gastrointestinal nutrient sensing pathways provides a promising a new approach for the treatment of metabolic diseases including diabetes and obesity. The calcium-sensing receptor has been identified as a key receptor involved in mineral and amino acid nutrient sensing and thus is an attractive target for modulation in the intestine. Herein we describe the optimization of gastrointestinally restricted calcium-sensing receptor agonists starting from a 3-aminopyrrolidine-containing template leading to the identification of GI-restricted agonist 19 (GSK3004774).</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>28916340</pmid><doi>10.1016/j.bmcl.2017.09.008</doi><tpages>5</tpages></addata></record> |
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| identifier | ISSN: 0960-894X |
| ispartof | Bioorganic & medicinal chemistry letters, 2017-10, Vol.27 (20), p.4673-4677 |
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| language | eng |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Calcium - metabolism Calcium sensing receptor Cell Membrane Permeability - drug effects Dogs Gastrointestinal Tract - metabolism GI-restricted HEK293 Cells Humans Madin Darby Canine Kidney Cells Nutrient sensing Pyrrolidines - chemistry Pyrrolidines - metabolism Pyrrolidines - pharmacology Receptors, Calcium-Sensing - agonists Receptors, Calcium-Sensing - genetics Receptors, Calcium-Sensing - metabolism Structure-Activity Relationship |
| title | Identification of potent, nonabsorbable agonists of the calcium-sensing receptor for GI-specific administration |
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