Discovery of 7-azaindole derivatives as potent Orai inhibitors showing efficacy in a preclinical model of asthma
[Display omitted] Synthesis and SAR of a series of 7-azaindoles as Orai channel inhibitors showing good potency inhibiting IL-2 production in Jurkat cells is described. Compound 14d displaying best pharmacokinetic properties was further characterized in a model of allergen induced asthma showing inh...
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| Veröffentlicht in: | Bioorganic & medicinal chemistry letters 2015-03, Vol.25 (6), p.1217-1222 |
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| container_title | Bioorganic & medicinal chemistry letters |
| container_volume | 25 |
| creator | Esteve, Cristina González, Jacob Gual, Sílvia Vidal, Laura Alzina, Soledad Sentellas, Sonia Jover, Irene Horrillo, Raquel De Alba, Jorge Miralpeix, Montserrat Tarrasón, Gema Vidal, Bernat |
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Synthesis and SAR of a series of 7-azaindoles as Orai channel inhibitors showing good potency inhibiting IL-2 production in Jurkat cells is described. Compound 14d displaying best pharmacokinetic properties was further characterized in a model of allergen induced asthma showing inhibition in the number of eosinophils in BALF. High lipophilicity remains as one of the main challenges for this class of compounds. |
| doi_str_mv | 10.1016/j.bmcl.2015.01.063 |
| format | Article |
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Synthesis and SAR of a series of 7-azaindoles as Orai channel inhibitors showing good potency inhibiting IL-2 production in Jurkat cells is described. Compound 14d displaying best pharmacokinetic properties was further characterized in a model of allergen induced asthma showing inhibition in the number of eosinophils in BALF. High lipophilicity remains as one of the main challenges for this class of compounds.</description><identifier>ISSN: 0960-894X</identifier><identifier>EISSN: 1464-3405</identifier><identifier>DOI: 10.1016/j.bmcl.2015.01.063</identifier><identifier>PMID: 25690784</identifier><language>eng</language><publisher>England: Elsevier Ltd</publisher><subject>Animals ; Asthma ; Aza Compounds - chemistry ; Calcium Channel Blockers - chemistry ; Calcium Channel Blockers - pharmacokinetics ; Calcium Channel Blockers - therapeutic use ; Calcium Channels - chemistry ; Calcium Channels - metabolism ; CRAC channel ; Disease Models, Animal ; Drug Evaluation, Preclinical ; Half-Life ; Humans ; Hypersensitivity - drug therapy ; Hypersensitivity - immunology ; IL-2 inhibitors ; Indoles - chemistry ; Indoles - pharmacokinetics ; Indoles - therapeutic use ; Interleukin-2 - blood ; Interleukin-2 - metabolism ; Jurkat Cells ; LAD2 ; Microsomes - metabolism ; Models, Biological ; Orai inhibitors ; OVA model ; Ovalbumin - immunology ; Protein Binding ; Pyridines - chemistry ; Pyridines - pharmacokinetics ; Pyridines - therapeutic use ; Pyrroles - chemistry ; Pyrroles - pharmacokinetics ; Pyrroles - therapeutic use ; Rats ; Structure-Activity Relationship</subject><ispartof>Bioorganic & medicinal chemistry letters, 2015-03, Vol.25 (6), p.1217-1222</ispartof><rights>2015 Elsevier Ltd</rights><rights>Copyright © 2015 Elsevier Ltd. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c426t-96eb3ab700eb56e5bee4d72ea34635e7c2147f7f8f2f7361a064ba176e444ddd3</citedby><cites>FETCH-LOGICAL-c426t-96eb3ab700eb56e5bee4d72ea34635e7c2147f7f8f2f7361a064ba176e444ddd3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://www.sciencedirect.com/science/article/pii/S0960894X15000840$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,776,780,3537,27901,27902,65306</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/25690784$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Esteve, Cristina</creatorcontrib><creatorcontrib>González, Jacob</creatorcontrib><creatorcontrib>Gual, Sílvia</creatorcontrib><creatorcontrib>Vidal, Laura</creatorcontrib><creatorcontrib>Alzina, Soledad</creatorcontrib><creatorcontrib>Sentellas, Sonia</creatorcontrib><creatorcontrib>Jover, Irene</creatorcontrib><creatorcontrib>Horrillo, Raquel</creatorcontrib><creatorcontrib>De Alba, Jorge</creatorcontrib><creatorcontrib>Miralpeix, Montserrat</creatorcontrib><creatorcontrib>Tarrasón, Gema</creatorcontrib><creatorcontrib>Vidal, Bernat</creatorcontrib><title>Discovery of 7-azaindole derivatives as potent Orai inhibitors showing efficacy in a preclinical model of asthma</title><title>Bioorganic & medicinal chemistry letters</title><addtitle>Bioorg Med Chem Lett</addtitle><description>[Display omitted]
Synthesis and SAR of a series of 7-azaindoles as Orai channel inhibitors showing good potency inhibiting IL-2 production in Jurkat cells is described. Compound 14d displaying best pharmacokinetic properties was further characterized in a model of allergen induced asthma showing inhibition in the number of eosinophils in BALF. High lipophilicity remains as one of the main challenges for this class of compounds.</description><subject>Animals</subject><subject>Asthma</subject><subject>Aza Compounds - chemistry</subject><subject>Calcium Channel Blockers - chemistry</subject><subject>Calcium Channel Blockers - pharmacokinetics</subject><subject>Calcium Channel Blockers - therapeutic use</subject><subject>Calcium Channels - chemistry</subject><subject>Calcium Channels - metabolism</subject><subject>CRAC channel</subject><subject>Disease Models, Animal</subject><subject>Drug Evaluation, Preclinical</subject><subject>Half-Life</subject><subject>Humans</subject><subject>Hypersensitivity - drug therapy</subject><subject>Hypersensitivity - immunology</subject><subject>IL-2 inhibitors</subject><subject>Indoles - chemistry</subject><subject>Indoles - pharmacokinetics</subject><subject>Indoles - therapeutic use</subject><subject>Interleukin-2 - blood</subject><subject>Interleukin-2 - metabolism</subject><subject>Jurkat Cells</subject><subject>LAD2</subject><subject>Microsomes - metabolism</subject><subject>Models, Biological</subject><subject>Orai inhibitors</subject><subject>OVA model</subject><subject>Ovalbumin - immunology</subject><subject>Protein Binding</subject><subject>Pyridines - chemistry</subject><subject>Pyridines - pharmacokinetics</subject><subject>Pyridines - therapeutic use</subject><subject>Pyrroles - chemistry</subject><subject>Pyrroles - pharmacokinetics</subject><subject>Pyrroles - therapeutic use</subject><subject>Rats</subject><subject>Structure-Activity Relationship</subject><issn>0960-894X</issn><issn>1464-3405</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2015</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kMFq3DAQhkVIyG7TvkAPQcdc7IxsWVpDLyVNmkIglwR6E7I06mqxLUfybtk-fbXstsecBma-_4f5CPnMoGTAxO2m7AbTlxWwpgRWgqjPyJJxwYuaQ3NOltAKKFYt_7kgH1LaADAOnF-SRdWIFuSKL8n0zScTdhj3NDgqC_1H-9GGHqnF6Hd69jtMVCc6hRnHmT5H7akf177zc4iJpnX47cdfFJ3zRpt9vlFNp4im92Pe9HQIFvtDuU7zetAfyYXTfcJPp3lFXh_uX-4ei6fn7z_uvj4VhldiLlqBXa07CYBdI7DpELmVFeqai7pBaSrGpZNu5Sona8E0CN5pJgVyzq219RW5OfZOMbxtMc1qyJ9i3-sRwzYpJgSIpm1amdHqiJoYUoro1BT9oONeMVAH02qjDqbVwbQCprLpHLo-9W-7Ae3_yD-1GfhyBDB_ufMYVTIeR4PWZzuzssG_1_8XMouRBg</recordid><startdate>20150315</startdate><enddate>20150315</enddate><creator>Esteve, Cristina</creator><creator>González, Jacob</creator><creator>Gual, Sílvia</creator><creator>Vidal, Laura</creator><creator>Alzina, Soledad</creator><creator>Sentellas, Sonia</creator><creator>Jover, Irene</creator><creator>Horrillo, Raquel</creator><creator>De Alba, Jorge</creator><creator>Miralpeix, Montserrat</creator><creator>Tarrasón, Gema</creator><creator>Vidal, Bernat</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>20150315</creationdate><title>Discovery of 7-azaindole derivatives as potent Orai inhibitors showing efficacy in a preclinical model of asthma</title><author>Esteve, Cristina ; González, Jacob ; Gual, Sílvia ; Vidal, Laura ; Alzina, Soledad ; Sentellas, Sonia ; Jover, Irene ; Horrillo, Raquel ; De Alba, Jorge ; Miralpeix, Montserrat ; Tarrasón, Gema ; Vidal, Bernat</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c426t-96eb3ab700eb56e5bee4d72ea34635e7c2147f7f8f2f7361a064ba176e444ddd3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2015</creationdate><topic>Animals</topic><topic>Asthma</topic><topic>Aza Compounds - chemistry</topic><topic>Calcium Channel Blockers - chemistry</topic><topic>Calcium Channel Blockers - pharmacokinetics</topic><topic>Calcium Channel Blockers - therapeutic use</topic><topic>Calcium Channels - chemistry</topic><topic>Calcium Channels - metabolism</topic><topic>CRAC channel</topic><topic>Disease Models, Animal</topic><topic>Drug Evaluation, Preclinical</topic><topic>Half-Life</topic><topic>Humans</topic><topic>Hypersensitivity - drug therapy</topic><topic>Hypersensitivity - immunology</topic><topic>IL-2 inhibitors</topic><topic>Indoles - chemistry</topic><topic>Indoles - pharmacokinetics</topic><topic>Indoles - therapeutic use</topic><topic>Interleukin-2 - blood</topic><topic>Interleukin-2 - metabolism</topic><topic>Jurkat Cells</topic><topic>LAD2</topic><topic>Microsomes - metabolism</topic><topic>Models, Biological</topic><topic>Orai inhibitors</topic><topic>OVA model</topic><topic>Ovalbumin - immunology</topic><topic>Protein Binding</topic><topic>Pyridines - chemistry</topic><topic>Pyridines - pharmacokinetics</topic><topic>Pyridines - therapeutic use</topic><topic>Pyrroles - chemistry</topic><topic>Pyrroles - pharmacokinetics</topic><topic>Pyrroles - therapeutic use</topic><topic>Rats</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Esteve, Cristina</creatorcontrib><creatorcontrib>González, Jacob</creatorcontrib><creatorcontrib>Gual, Sílvia</creatorcontrib><creatorcontrib>Vidal, Laura</creatorcontrib><creatorcontrib>Alzina, Soledad</creatorcontrib><creatorcontrib>Sentellas, Sonia</creatorcontrib><creatorcontrib>Jover, Irene</creatorcontrib><creatorcontrib>Horrillo, Raquel</creatorcontrib><creatorcontrib>De Alba, Jorge</creatorcontrib><creatorcontrib>Miralpeix, Montserrat</creatorcontrib><creatorcontrib>Tarrasón, Gema</creatorcontrib><creatorcontrib>Vidal, Bernat</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>Esteve, Cristina</au><au>González, Jacob</au><au>Gual, Sílvia</au><au>Vidal, Laura</au><au>Alzina, Soledad</au><au>Sentellas, Sonia</au><au>Jover, Irene</au><au>Horrillo, Raquel</au><au>De Alba, Jorge</au><au>Miralpeix, Montserrat</au><au>Tarrasón, Gema</au><au>Vidal, Bernat</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of 7-azaindole derivatives as potent Orai inhibitors showing efficacy in a preclinical model of asthma</atitle><jtitle>Bioorganic & medicinal chemistry letters</jtitle><addtitle>Bioorg Med Chem Lett</addtitle><date>2015-03-15</date><risdate>2015</risdate><volume>25</volume><issue>6</issue><spage>1217</spage><epage>1222</epage><pages>1217-1222</pages><issn>0960-894X</issn><eissn>1464-3405</eissn><abstract>[Display omitted]
Synthesis and SAR of a series of 7-azaindoles as Orai channel inhibitors showing good potency inhibiting IL-2 production in Jurkat cells is described. Compound 14d displaying best pharmacokinetic properties was further characterized in a model of allergen induced asthma showing inhibition in the number of eosinophils in BALF. High lipophilicity remains as one of the main challenges for this class of compounds.</abstract><cop>England</cop><pub>Elsevier Ltd</pub><pmid>25690784</pmid><doi>10.1016/j.bmcl.2015.01.063</doi><tpages>6</tpages></addata></record> |
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| ispartof | Bioorganic & medicinal chemistry letters, 2015-03, Vol.25 (6), p.1217-1222 |
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| source | MEDLINE; Elsevier ScienceDirect Journals |
| subjects | Animals Asthma Aza Compounds - chemistry Calcium Channel Blockers - chemistry Calcium Channel Blockers - pharmacokinetics Calcium Channel Blockers - therapeutic use Calcium Channels - chemistry Calcium Channels - metabolism CRAC channel Disease Models, Animal Drug Evaluation, Preclinical Half-Life Humans Hypersensitivity - drug therapy Hypersensitivity - immunology IL-2 inhibitors Indoles - chemistry Indoles - pharmacokinetics Indoles - therapeutic use Interleukin-2 - blood Interleukin-2 - metabolism Jurkat Cells LAD2 Microsomes - metabolism Models, Biological Orai inhibitors OVA model Ovalbumin - immunology Protein Binding Pyridines - chemistry Pyridines - pharmacokinetics Pyridines - therapeutic use Pyrroles - chemistry Pyrroles - pharmacokinetics Pyrroles - therapeutic use Rats Structure-Activity Relationship |
| title | Discovery of 7-azaindole derivatives as potent Orai inhibitors showing efficacy in a preclinical model of asthma |
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