Synthesis and SAR of 5-Amino- and 5-(Aminomethyl)benzofuran Histamine H3 Receptor Antagonists with Improved Potency
A new series of H3 receptor antagonists was discovered with nanomolar and subnanomolar affinities at human and rat H3 receptors. Starting from an earlier, more structurally limited series of benzofurans, the present series of compounds demonstrated increased structural variety and flexibility with g...
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| Veröffentlicht in: | Journal of medicinal chemistry 2005-10, Vol.48 (20), p.6482-6490 |
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| container_title | Journal of medicinal chemistry |
| container_volume | 48 |
| creator | Sun, Minghua Zhao, Chen Gfesser, Gregory A Thiffault, Christine Miller, Thomas R Marsh, Kennan Wetter, Jill Curtis, Michael Faghih, Ramin Esbenshade, Timothy A Hancock, Arthur A Cowart, Marlon |
| description | A new series of H3 receptor antagonists was discovered with nanomolar and subnanomolar affinities at human and rat H3 receptors. Starting from an earlier, more structurally limited series of benzofurans, the present series of compounds demonstrated increased structural variety and flexibility with greater in vitro potency. One compound in particular, {2-[2-(2-(R)-methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl}(5-nitropyridin-2-yl)amine (7h), gave the best binding potency (human K i of 0.05 nM, rat K i of 0.11 nM), which represented a 9-fold (in human) and an 11-fold (in rat) improvement over ABT-239 (compound 5), a compound previously reported to have excellent in vitro potency and in vivo efficacy. The synthesis, SAR of the H3 binding affinities, in vitro assay for phospholipidosis, and pharmacokinetic properties of the new compounds are described. |
| doi_str_mv | 10.1021/jm0504398 |
| format | Article |
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Starting from an earlier, more structurally limited series of benzofurans, the present series of compounds demonstrated increased structural variety and flexibility with greater in vitro potency. One compound in particular, {2-[2-(2-(R)-methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl}(5-nitropyridin-2-yl)amine (7h), gave the best binding potency (human K i of 0.05 nM, rat K i of 0.11 nM), which represented a 9-fold (in human) and an 11-fold (in rat) improvement over ABT-239 (compound 5), a compound previously reported to have excellent in vitro potency and in vivo efficacy. The synthesis, SAR of the H3 binding affinities, in vitro assay for phospholipidosis, and pharmacokinetic properties of the new compounds are described.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm0504398</identifier><identifier>PMID: 16190774</identifier><identifier>CODEN: JMCMAR</identifier><language>eng</language><publisher>Washington, DC: American Chemical Society</publisher><subject>Animals ; Benzofurans - chemical synthesis ; Benzofurans - pharmacokinetics ; Benzofurans - pharmacology ; Biological and medical sciences ; Cells, Cultured ; Hepatocytes - drug effects ; Hepatocytes - metabolism ; Histamine Antagonists - chemical synthesis ; Histamine Antagonists - pharmacokinetics ; Histamine Antagonists - pharmacology ; Humans ; Male ; Medical sciences ; Miscellaneous ; Neuropharmacology ; Neurotransmitters. Neurotransmission. Receptors ; Pharmacology. Drug treatments ; Phospholipids - biosynthesis ; Pyrrolidines - chemical synthesis ; Pyrrolidines - pharmacokinetics ; Pyrrolidines - pharmacology ; Radioligand Assay ; Rats ; Rats, Sprague-Dawley ; Receptors, Histamine H3 - drug effects ; Receptors, Histamine H3 - metabolism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2005-10, Vol.48 (20), p.6482-6490</ispartof><rights>Copyright © 2005 American Chemical Society</rights><rights>2006 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/jm0504398$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm0504398$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=17165202$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/16190774$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Sun, Minghua</creatorcontrib><creatorcontrib>Zhao, Chen</creatorcontrib><creatorcontrib>Gfesser, Gregory A</creatorcontrib><creatorcontrib>Thiffault, Christine</creatorcontrib><creatorcontrib>Miller, Thomas R</creatorcontrib><creatorcontrib>Marsh, Kennan</creatorcontrib><creatorcontrib>Wetter, Jill</creatorcontrib><creatorcontrib>Curtis, Michael</creatorcontrib><creatorcontrib>Faghih, Ramin</creatorcontrib><creatorcontrib>Esbenshade, Timothy A</creatorcontrib><creatorcontrib>Hancock, Arthur A</creatorcontrib><creatorcontrib>Cowart, Marlon</creatorcontrib><title>Synthesis and SAR of 5-Amino- and 5-(Aminomethyl)benzofuran Histamine H3 Receptor Antagonists with Improved Potency</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A new series of H3 receptor antagonists was discovered with nanomolar and subnanomolar affinities at human and rat H3 receptors. Starting from an earlier, more structurally limited series of benzofurans, the present series of compounds demonstrated increased structural variety and flexibility with greater in vitro potency. One compound in particular, {2-[2-(2-(R)-methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl}(5-nitropyridin-2-yl)amine (7h), gave the best binding potency (human K i of 0.05 nM, rat K i of 0.11 nM), which represented a 9-fold (in human) and an 11-fold (in rat) improvement over ABT-239 (compound 5), a compound previously reported to have excellent in vitro potency and in vivo efficacy. The synthesis, SAR of the H3 binding affinities, in vitro assay for phospholipidosis, and pharmacokinetic properties of the new compounds are described.</description><subject>Animals</subject><subject>Benzofurans - chemical synthesis</subject><subject>Benzofurans - pharmacokinetics</subject><subject>Benzofurans - pharmacology</subject><subject>Biological and medical sciences</subject><subject>Cells, Cultured</subject><subject>Hepatocytes - drug effects</subject><subject>Hepatocytes - metabolism</subject><subject>Histamine Antagonists - chemical synthesis</subject><subject>Histamine Antagonists - pharmacokinetics</subject><subject>Histamine Antagonists - pharmacology</subject><subject>Humans</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Miscellaneous</subject><subject>Neuropharmacology</subject><subject>Neurotransmitters. Neurotransmission. Receptors</subject><subject>Pharmacology. Drug treatments</subject><subject>Phospholipids - biosynthesis</subject><subject>Pyrrolidines - chemical synthesis</subject><subject>Pyrrolidines - pharmacokinetics</subject><subject>Pyrrolidines - pharmacology</subject><subject>Radioligand Assay</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Histamine H3 - drug effects</subject><subject>Receptors, Histamine H3 - metabolism</subject><subject>Structure-Activity Relationship</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>eNpFkU1vEzEQhi1ERUPhwB9AvlDRg4u_1t49RlFLiiL1I-HCxfLa3mbTXTtdewvh19e0oT2NZt5HM3rfAeATwacEU_Jt0-MCc1aVb8CEFBQjXmL-FkwwphRRQdkheB_jBmPMCGXvwCERpMJS8gmIy51PaxfbCLW3cDm9gaGBBZr2rQ_oaVagr09d79J6153Uzv8NzThoD-dtTDpLDs4ZvHHGbVMY4NQnfRt81iL83aY1vOi3Q3hwFl6F5LzZfQAHje6i-7ivR-Dn-dlqNkeLy-8Xs-kCaUppQqSwdV0Z0gjNKbeYVcSIuhS1xbVhhBvLK6qlkJbYQjJnMNHWGVKKpjJUEnYEjp_35vP3o4tJ9W00ruu0d2GMSpSCc4mrDH7eg2PdO6u2Q9vrYaf-x5SBL3tAR6O7Jps3bXzlJBE5dpo59Mxl8-7Pi66HOyUkk4VaXS1Vtfg1-7E8X6nr173aRLUJ4-BzHopg9e-t6uWt7BFtK5Bf</recordid><startdate>20051006</startdate><enddate>20051006</enddate><creator>Sun, Minghua</creator><creator>Zhao, Chen</creator><creator>Gfesser, Gregory A</creator><creator>Thiffault, Christine</creator><creator>Miller, Thomas R</creator><creator>Marsh, Kennan</creator><creator>Wetter, Jill</creator><creator>Curtis, Michael</creator><creator>Faghih, Ramin</creator><creator>Esbenshade, Timothy A</creator><creator>Hancock, Arthur A</creator><creator>Cowart, Marlon</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>20051006</creationdate><title>Synthesis and SAR of 5-Amino- and 5-(Aminomethyl)benzofuran Histamine H3 Receptor Antagonists with Improved Potency</title><author>Sun, Minghua ; Zhao, Chen ; Gfesser, Gregory A ; Thiffault, Christine ; Miller, Thomas R ; Marsh, Kennan ; Wetter, Jill ; Curtis, Michael ; Faghih, Ramin ; Esbenshade, Timothy A ; Hancock, Arthur A ; Cowart, Marlon</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a222t-15dbb9c1f6a424d0391c6b86bd0bc314cd492a767d1d573ec01adec186f9c2713</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2005</creationdate><topic>Animals</topic><topic>Benzofurans - chemical synthesis</topic><topic>Benzofurans - pharmacokinetics</topic><topic>Benzofurans - pharmacology</topic><topic>Biological and medical sciences</topic><topic>Cells, Cultured</topic><topic>Hepatocytes - drug effects</topic><topic>Hepatocytes - metabolism</topic><topic>Histamine Antagonists - chemical synthesis</topic><topic>Histamine Antagonists - pharmacokinetics</topic><topic>Histamine Antagonists - pharmacology</topic><topic>Humans</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Miscellaneous</topic><topic>Neuropharmacology</topic><topic>Neurotransmitters. Neurotransmission. Receptors</topic><topic>Pharmacology. Drug treatments</topic><topic>Phospholipids - biosynthesis</topic><topic>Pyrrolidines - chemical synthesis</topic><topic>Pyrrolidines - pharmacokinetics</topic><topic>Pyrrolidines - pharmacology</topic><topic>Radioligand Assay</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Histamine H3 - drug effects</topic><topic>Receptors, Histamine H3 - metabolism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Sun, Minghua</creatorcontrib><creatorcontrib>Zhao, Chen</creatorcontrib><creatorcontrib>Gfesser, Gregory A</creatorcontrib><creatorcontrib>Thiffault, Christine</creatorcontrib><creatorcontrib>Miller, Thomas R</creatorcontrib><creatorcontrib>Marsh, Kennan</creatorcontrib><creatorcontrib>Wetter, Jill</creatorcontrib><creatorcontrib>Curtis, Michael</creatorcontrib><creatorcontrib>Faghih, Ramin</creatorcontrib><creatorcontrib>Esbenshade, Timothy A</creatorcontrib><creatorcontrib>Hancock, Arthur A</creatorcontrib><creatorcontrib>Cowart, Marlon</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>Sun, Minghua</au><au>Zhao, Chen</au><au>Gfesser, Gregory A</au><au>Thiffault, Christine</au><au>Miller, Thomas R</au><au>Marsh, Kennan</au><au>Wetter, Jill</au><au>Curtis, Michael</au><au>Faghih, Ramin</au><au>Esbenshade, Timothy A</au><au>Hancock, Arthur A</au><au>Cowart, Marlon</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Synthesis and SAR of 5-Amino- and 5-(Aminomethyl)benzofuran Histamine H3 Receptor Antagonists with Improved Potency</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2005-10-06</date><risdate>2005</risdate><volume>48</volume><issue>20</issue><spage>6482</spage><epage>6490</epage><pages>6482-6490</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><coden>JMCMAR</coden><abstract>A new series of H3 receptor antagonists was discovered with nanomolar and subnanomolar affinities at human and rat H3 receptors. Starting from an earlier, more structurally limited series of benzofurans, the present series of compounds demonstrated increased structural variety and flexibility with greater in vitro potency. One compound in particular, {2-[2-(2-(R)-methylpyrrolidin-1-yl)ethyl]benzofuran-5-yl}(5-nitropyridin-2-yl)amine (7h), gave the best binding potency (human K i of 0.05 nM, rat K i of 0.11 nM), which represented a 9-fold (in human) and an 11-fold (in rat) improvement over ABT-239 (compound 5), a compound previously reported to have excellent in vitro potency and in vivo efficacy. The synthesis, SAR of the H3 binding affinities, in vitro assay for phospholipidosis, and pharmacokinetic properties of the new compounds are described.</abstract><cop>Washington, DC</cop><pub>American Chemical Society</pub><pmid>16190774</pmid><doi>10.1021/jm0504398</doi><tpages>9</tpages></addata></record> |
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| subjects | Animals Benzofurans - chemical synthesis Benzofurans - pharmacokinetics Benzofurans - pharmacology Biological and medical sciences Cells, Cultured Hepatocytes - drug effects Hepatocytes - metabolism Histamine Antagonists - chemical synthesis Histamine Antagonists - pharmacokinetics Histamine Antagonists - pharmacology Humans Male Medical sciences Miscellaneous Neuropharmacology Neurotransmitters. Neurotransmission. Receptors Pharmacology. Drug treatments Phospholipids - biosynthesis Pyrrolidines - chemical synthesis Pyrrolidines - pharmacokinetics Pyrrolidines - pharmacology Radioligand Assay Rats Rats, Sprague-Dawley Receptors, Histamine H3 - drug effects Receptors, Histamine H3 - metabolism Structure-Activity Relationship |
| title | Synthesis and SAR of 5-Amino- and 5-(Aminomethyl)benzofuran Histamine H3 Receptor Antagonists with Improved Potency |
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