6-Aryl-8H-indeno[1,2-d]thiazol-2-ylamines: A1 Adenosine Receptor Agonist Allosteric Enhancers Having Improved Potency
Allosteric enhancers (AEs) of the A1 adenosine receptor (A1AR) have potential as drugs for treating neurological, cardiovascular, and renal diseases. This report describes the synthesis and evaluation of a series of 6-aryl-8H-indeno[1,2-d]thiazol-2-ylamines that exhibited AE activity at the A1AR. Pa...
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| Veröffentlicht in: | Journal of medicinal chemistry 2005-08, Vol.48 (16), p.5131-5139 |
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| container_title | Journal of medicinal chemistry |
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| creator | Chordia, Mahendra D Zigler, Molly Murphree, Lauren J Figler, Heidi Macdonald, Timothy L Olsson, Ray A Linden, Joel |
| description | Allosteric enhancers (AEs) of the A1 adenosine receptor (A1AR) have potential as drugs for treating neurological, cardiovascular, and renal diseases. This report describes the synthesis and evaluation of a series of 6-aryl-8H-indeno[1,2-d]thiazol-2-ylamines that exhibited AE activity at the A1AR. Palladium-mediated condensation of arylboronic acids with 5-bromoindan-1-one generated arylindanones 2a − aj for iodine-catalyzed condensation with thiourea, generating 2-aminothiazolium salts 3a − aj. Binding studies using membranes from cells stably expressing human A1ARs, A2AARs, or A3ARs evaluated AE activity and receptor subtype selectivity. The EC50 of the AE activities of compounds 3m − o, 3x, and 3ae were 2.2, 1.5, 0.9, 1.0, and 3.0 μM, respectively, substantially lower than that of the well characterized 2-amino-3-aroylthiophene (PD 81,723), >10 μM. The new compounds also have substantially higher maximal AE activity. These compounds had no AE activity at the A2AAR and only minimal activity at the A3AR. |
| doi_str_mv | 10.1021/jm049132j |
| format | Article |
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This report describes the synthesis and evaluation of a series of 6-aryl-8H-indeno[1,2-d]thiazol-2-ylamines that exhibited AE activity at the A1AR. Palladium-mediated condensation of arylboronic acids with 5-bromoindan-1-one generated arylindanones 2a − aj for iodine-catalyzed condensation with thiourea, generating 2-aminothiazolium salts 3a − aj. Binding studies using membranes from cells stably expressing human A1ARs, A2AARs, or A3ARs evaluated AE activity and receptor subtype selectivity. The EC50 of the AE activities of compounds 3m − o, 3x, and 3ae were 2.2, 1.5, 0.9, 1.0, and 3.0 μM, respectively, substantially lower than that of the well characterized 2-amino-3-aroylthiophene (PD 81,723), >10 μM. The new compounds also have substantially higher maximal AE activity. These compounds had no AE activity at the A2AAR and only minimal activity at the A3AR.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm049132j</identifier><identifier>PMID: 16078833</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Adenosine A1 Receptor Agonists ; Adenosine A1 Receptor Antagonists ; Allosteric Regulation ; Amines - chemical synthesis ; Amines - chemistry ; Amines - pharmacology ; Animals ; Binding, Competitive ; Biological and medical sciences ; Cell Line ; Cricetinae ; Cricetulus ; Humans ; Indenes - chemical synthesis ; Indenes - chemistry ; Indenes - pharmacology ; Medical sciences ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems ; Pharmacology. Drug treatments ; Radioligand Assay ; Structure-Activity Relationship ; Thiazoles - chemical synthesis ; Thiazoles - chemistry ; Thiazoles - pharmacology</subject><ispartof>Journal of medicinal chemistry, 2005-08, Vol.48 (16), p.5131-5139</ispartof><rights>Copyright © 2005 American Chemical Society</rights><rights>2005 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm049132j$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm049132j$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,778,782,27059,27907,27908,56721,56771</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17021595$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16078833$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Chordia, Mahendra D</creatorcontrib><creatorcontrib>Zigler, Molly</creatorcontrib><creatorcontrib>Murphree, Lauren J</creatorcontrib><creatorcontrib>Figler, Heidi</creatorcontrib><creatorcontrib>Macdonald, Timothy L</creatorcontrib><creatorcontrib>Olsson, Ray A</creatorcontrib><creatorcontrib>Linden, Joel</creatorcontrib><title>6-Aryl-8H-indeno[1,2-d]thiazol-2-ylamines: A1 Adenosine Receptor Agonist Allosteric Enhancers Having Improved Potency</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Allosteric enhancers (AEs) of the A1 adenosine receptor (A1AR) have potential as drugs for treating neurological, cardiovascular, and renal diseases. This report describes the synthesis and evaluation of a series of 6-aryl-8H-indeno[1,2-d]thiazol-2-ylamines that exhibited AE activity at the A1AR. Palladium-mediated condensation of arylboronic acids with 5-bromoindan-1-one generated arylindanones 2a − aj for iodine-catalyzed condensation with thiourea, generating 2-aminothiazolium salts 3a − aj. Binding studies using membranes from cells stably expressing human A1ARs, A2AARs, or A3ARs evaluated AE activity and receptor subtype selectivity. The EC50 of the AE activities of compounds 3m − o, 3x, and 3ae were 2.2, 1.5, 0.9, 1.0, and 3.0 μM, respectively, substantially lower than that of the well characterized 2-amino-3-aroylthiophene (PD 81,723), >10 μM. The new compounds also have substantially higher maximal AE activity. These compounds had no AE activity at the A2AAR and only minimal activity at the A3AR.</description><subject>Adenosine A1 Receptor Agonists</subject><subject>Adenosine A1 Receptor Antagonists</subject><subject>Allosteric Regulation</subject><subject>Amines - chemical synthesis</subject><subject>Amines - chemistry</subject><subject>Amines - pharmacology</subject><subject>Animals</subject><subject>Binding, Competitive</subject><subject>Biological and medical sciences</subject><subject>Cell Line</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Humans</subject><subject>Indenes - chemical synthesis</subject><subject>Indenes - chemistry</subject><subject>Indenes - pharmacology</subject><subject>Medical sciences</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</subject><subject>Pharmacology. Drug treatments</subject><subject>Radioligand Assay</subject><subject>Structure-Activity Relationship</subject><subject>Thiazoles - chemical synthesis</subject><subject>Thiazoles - chemistry</subject><subject>Thiazoles - pharmacology</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2005</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpFkUFvEzEQhS0EoqHlwB9AvsAJgz3etb3clqhtKirRltwQshyv0zp4vcHeVA0nrvzN_pK6amhPI8379EbzHkJvGP3IKLBPq55WDeOweoYmrAZKKkWr52hCKQABAXwPvcp5RSnlDPhLtMcElUpxPkE3grRpG4iaER87F4cf7AOQ7ud45c2fIRAg22B6H13-fPv3H24Zbu-pXDb4wlm3HoeE28sh-jziNoQhjy55iw_jlYnWpYxn5trHS3zSr9Nw7Tp8Nowu2u0BerE0IbvXu7mP5keH8-mMnH47Ppm2p8QAwEgkLMuLTghlmLRQV8CrJZNMqI421ApGi8SaWoLlVi3EQnDaARVW1a5ZOL6P3j_Yluu_Ny6PuvfZuhBMdMMma6GqSlVSFfDtDtwsetfpdfK9SVv9P6oCvNsBJlsTlqn85_MTJ0sTdVMXjjxwJRF386ib9EsLyWWt52ff9fGRmn5RXy_0-ZOvsVmvhk2KJQ7NqL6vVj9Wy-8AjBeQ6A</recordid><startdate>20050811</startdate><enddate>20050811</enddate><creator>Chordia, Mahendra D</creator><creator>Zigler, Molly</creator><creator>Murphree, Lauren J</creator><creator>Figler, Heidi</creator><creator>Macdonald, Timothy L</creator><creator>Olsson, Ray A</creator><creator>Linden, Joel</creator><general>American Chemical Society</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>7X8</scope></search><sort><creationdate>20050811</creationdate><title>6-Aryl-8H-indeno[1,2-d]thiazol-2-ylamines: A1 Adenosine Receptor Agonist Allosteric Enhancers Having Improved Potency</title><author>Chordia, Mahendra D ; Zigler, Molly ; Murphree, Lauren J ; Figler, Heidi ; Macdonald, Timothy L ; Olsson, Ray A ; Linden, Joel</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a222t-72f102e668a17c254234f17168d090c61066819572c3c8b6b630d206c85e9be3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Adenosine A1 Receptor Agonists</topic><topic>Adenosine A1 Receptor Antagonists</topic><topic>Allosteric Regulation</topic><topic>Amines - chemical synthesis</topic><topic>Amines - chemistry</topic><topic>Amines - pharmacology</topic><topic>Animals</topic><topic>Binding, Competitive</topic><topic>Biological and medical sciences</topic><topic>Cell Line</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Humans</topic><topic>Indenes - chemical synthesis</topic><topic>Indenes - chemistry</topic><topic>Indenes - pharmacology</topic><topic>Medical sciences</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems</topic><topic>Pharmacology. Drug treatments</topic><topic>Radioligand Assay</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>Chordia, Mahendra D</creatorcontrib><creatorcontrib>Zigler, Molly</creatorcontrib><creatorcontrib>Murphree, Lauren J</creatorcontrib><creatorcontrib>Figler, Heidi</creatorcontrib><creatorcontrib>Macdonald, Timothy L</creatorcontrib><creatorcontrib>Olsson, Ray A</creatorcontrib><creatorcontrib>Linden, Joel</creatorcontrib><collection>Istex</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>MEDLINE - Academic</collection><jtitle>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Chordia, Mahendra D</au><au>Zigler, Molly</au><au>Murphree, Lauren J</au><au>Figler, Heidi</au><au>Macdonald, Timothy L</au><au>Olsson, Ray A</au><au>Linden, Joel</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>6-Aryl-8H-indeno[1,2-d]thiazol-2-ylamines: A1 Adenosine Receptor Agonist Allosteric Enhancers Having Improved Potency</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2005-08-11</date><risdate>2005</risdate><volume>48</volume><issue>16</issue><spage>5131</spage><epage>5139</epage><pages>5131-5139</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>Allosteric enhancers (AEs) of the A1 adenosine receptor (A1AR) have potential as drugs for treating neurological, cardiovascular, and renal diseases. This report describes the synthesis and evaluation of a series of 6-aryl-8H-indeno[1,2-d]thiazol-2-ylamines that exhibited AE activity at the A1AR. Palladium-mediated condensation of arylboronic acids with 5-bromoindan-1-one generated arylindanones 2a − aj for iodine-catalyzed condensation with thiourea, generating 2-aminothiazolium salts 3a − aj. Binding studies using membranes from cells stably expressing human A1ARs, A2AARs, or A3ARs evaluated AE activity and receptor subtype selectivity. The EC50 of the AE activities of compounds 3m − o, 3x, and 3ae were 2.2, 1.5, 0.9, 1.0, and 3.0 μM, respectively, substantially lower than that of the well characterized 2-amino-3-aroylthiophene (PD 81,723), >10 μM. The new compounds also have substantially higher maximal AE activity. These compounds had no AE activity at the A2AAR and only minimal activity at the A3AR.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>16078833</pmid><doi>10.1021/jm049132j</doi><tpages>9</tpages></addata></record> |
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| subjects | Adenosine A1 Receptor Agonists Adenosine A1 Receptor Antagonists Allosteric Regulation Amines - chemical synthesis Amines - chemistry Amines - pharmacology Animals Binding, Competitive Biological and medical sciences Cell Line Cricetinae Cricetulus Humans Indenes - chemical synthesis Indenes - chemistry Indenes - pharmacology Medical sciences Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Peptidergic system (neuropeptide, opioid peptide, opiates...). Adenosinergic and purinergic systems Pharmacology. Drug treatments Radioligand Assay Structure-Activity Relationship Thiazoles - chemical synthesis Thiazoles - chemistry Thiazoles - pharmacology |
| title | 6-Aryl-8H-indeno[1,2-d]thiazol-2-ylamines: A1 Adenosine Receptor Agonist Allosteric Enhancers Having Improved Potency |
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