Discovery of Spirofused Piperazine and Diazepane Amides as Selective Histamine‑3 Antagonists with in Vivo Efficacy in a Mouse Model of Cognition
A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demons...
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| Veröffentlicht in: | Journal of medicinal chemistry 2014-02, Vol.57 (3), p.733-758 |
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| container_title | Journal of medicinal chemistry |
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| creator | Brown, Dean G Bernstein, Peter R Griffin, Andrew Wesolowski, Steve Labrecque, Denis Tremblay, Maxime C Sylvester, Mark Mauger, Russell Edwards, Phillip D Throner, Scott R Folmer, James J Cacciola, Joseph Scott, Clay Lazor, Lois A Pourashraf, Mehrnaz Santhakumar, Vijayaratnam Potts, William M Sydserff, Simon Giguère, Pascall Lévesque, Carine Dasser, Mohammed Groblewski, Thierry |
| description | A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only σ2 (62% at 10 μM). Compound 6s demonstrated free-plasma exposures above the IC50 (∼50×) with a brain-to-plasma ratio of ∼3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition. |
| doi_str_mv | 10.1021/jm4014828 |
| format | Article |
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Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only σ2 (62% at 10 μM). Compound 6s demonstrated free-plasma exposures above the IC50 (∼50×) with a brain-to-plasma ratio of ∼3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm4014828</identifier><identifier>PMID: 24410637</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Animals ; Azetidines - chemical synthesis ; Azetidines - pharmacokinetics ; Azetidines - pharmacology ; Cell Membrane Permeability ; CHO Cells ; Cognition - drug effects ; Cricetinae ; Cricetulus ; Cyclopropanes - chemical synthesis ; Cyclopropanes - pharmacokinetics ; Cyclopropanes - pharmacology ; Dogs ; Histamine H3 Antagonists - chemical synthesis ; Histamine H3 Antagonists - pharmacokinetics ; Histamine H3 Antagonists - pharmacology ; Humans ; Learning - drug effects ; Madin Darby Canine Kidney Cells ; Male ; Mice ; Microsomes, Liver - metabolism ; Models, Molecular ; Piperazines - chemical synthesis ; Piperazines - pharmacokinetics ; Piperazines - pharmacology ; Piperidines - chemical synthesis ; Piperidines - pharmacokinetics ; Piperidines - pharmacology ; Pyrrolidines - chemical synthesis ; Pyrrolidines - pharmacokinetics ; Pyrrolidines - pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Histamine H3 - genetics ; Receptors, Histamine H3 - metabolism ; Recognition (Psychology) - drug effects ; Spiro Compounds - chemical synthesis ; Spiro Compounds - pharmacokinetics ; Spiro Compounds - pharmacology ; Stereoisomerism ; Structure-Activity Relationship</subject><ispartof>Journal of medicinal chemistry, 2014-02, Vol.57 (3), p.733-758</ispartof><rights>Copyright © 2014 American Chemical Society</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-a315t-d0ae10f943ba7b7d8039b2d0c5f6b9efc03bc9aae8674c0e6db76f3383214f893</citedby><cites>FETCH-LOGICAL-a315t-d0ae10f943ba7b7d8039b2d0c5f6b9efc03bc9aae8674c0e6db76f3383214f893</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/jm4014828$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm4014828$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,2752,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/24410637$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Brown, Dean G</creatorcontrib><creatorcontrib>Bernstein, Peter R</creatorcontrib><creatorcontrib>Griffin, Andrew</creatorcontrib><creatorcontrib>Wesolowski, Steve</creatorcontrib><creatorcontrib>Labrecque, Denis</creatorcontrib><creatorcontrib>Tremblay, Maxime C</creatorcontrib><creatorcontrib>Sylvester, Mark</creatorcontrib><creatorcontrib>Mauger, Russell</creatorcontrib><creatorcontrib>Edwards, Phillip D</creatorcontrib><creatorcontrib>Throner, Scott R</creatorcontrib><creatorcontrib>Folmer, James J</creatorcontrib><creatorcontrib>Cacciola, Joseph</creatorcontrib><creatorcontrib>Scott, Clay</creatorcontrib><creatorcontrib>Lazor, Lois A</creatorcontrib><creatorcontrib>Pourashraf, Mehrnaz</creatorcontrib><creatorcontrib>Santhakumar, Vijayaratnam</creatorcontrib><creatorcontrib>Potts, William M</creatorcontrib><creatorcontrib>Sydserff, Simon</creatorcontrib><creatorcontrib>Giguère, Pascall</creatorcontrib><creatorcontrib>Lévesque, Carine</creatorcontrib><creatorcontrib>Dasser, Mohammed</creatorcontrib><creatorcontrib>Groblewski, Thierry</creatorcontrib><title>Discovery of Spirofused Piperazine and Diazepane Amides as Selective Histamine‑3 Antagonists with in Vivo Efficacy in a Mouse Model of Cognition</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only σ2 (62% at 10 μM). Compound 6s demonstrated free-plasma exposures above the IC50 (∼50×) with a brain-to-plasma ratio of ∼3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.</description><subject>Animals</subject><subject>Azetidines - chemical synthesis</subject><subject>Azetidines - pharmacokinetics</subject><subject>Azetidines - pharmacology</subject><subject>Cell Membrane Permeability</subject><subject>CHO Cells</subject><subject>Cognition - drug effects</subject><subject>Cricetinae</subject><subject>Cricetulus</subject><subject>Cyclopropanes - chemical synthesis</subject><subject>Cyclopropanes - pharmacokinetics</subject><subject>Cyclopropanes - pharmacology</subject><subject>Dogs</subject><subject>Histamine H3 Antagonists - chemical synthesis</subject><subject>Histamine H3 Antagonists - pharmacokinetics</subject><subject>Histamine H3 Antagonists - pharmacology</subject><subject>Humans</subject><subject>Learning - drug effects</subject><subject>Madin Darby Canine Kidney Cells</subject><subject>Male</subject><subject>Mice</subject><subject>Microsomes, Liver - metabolism</subject><subject>Models, Molecular</subject><subject>Piperazines - chemical synthesis</subject><subject>Piperazines - pharmacokinetics</subject><subject>Piperazines - pharmacology</subject><subject>Piperidines - chemical synthesis</subject><subject>Piperidines - pharmacokinetics</subject><subject>Piperidines - pharmacology</subject><subject>Pyrrolidines - chemical synthesis</subject><subject>Pyrrolidines - pharmacokinetics</subject><subject>Pyrrolidines - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Histamine H3 - genetics</subject><subject>Receptors, Histamine H3 - metabolism</subject><subject>Recognition (Psychology) - drug effects</subject><subject>Spiro Compounds - chemical synthesis</subject><subject>Spiro Compounds - pharmacokinetics</subject><subject>Spiro Compounds - pharmacology</subject><subject>Stereoisomerism</subject><subject>Structure-Activity Relationship</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2014</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNptkUtuFDEQhi0EIkNgwQWQN0hh0VB-TD-Wo0kgSEEgBdi2qu1y8Ki73dg9gyYrrgBH5CR4NCErNlWq0qf_rwdjzwW8FiDFm82gQeha1g_YQiwlFLoG_ZAtAKQsZCnVCXuS0gYAlJDqMTuRWgsoVbVgv899MmFHcc-D49eTj8FtE1n-yU8U8daPxHG0_NzjLU2Yq9XgLSWOiV9TT2b2O-KXPs04ZPbPz1-Kr8YZb8KYe4n_8PM37kf-1e8Cv3DOGzT7QwP5h5CNcrTUH7zX4Wb0sw_jU_bIYZ_o2V0-ZV_eXnxeXxZXH9-9X6-uClRiORcWkAS4RqsOq66yNaimkxbM0pVdQ86A6kyDSHVZaQNU2q4qnVK1kkK7ulGn7OyoO8XwfUtpbod8C-r7vGUerRW6aYSuskFGXx1RE0NKkVw7RT9g3LcC2sML2vsXZPbFney2G8jek_9unoGXRwBNajdhG8e85X-E_gIoD487</recordid><startdate>20140213</startdate><enddate>20140213</enddate><creator>Brown, Dean G</creator><creator>Bernstein, Peter R</creator><creator>Griffin, Andrew</creator><creator>Wesolowski, Steve</creator><creator>Labrecque, Denis</creator><creator>Tremblay, Maxime C</creator><creator>Sylvester, Mark</creator><creator>Mauger, Russell</creator><creator>Edwards, Phillip D</creator><creator>Throner, Scott R</creator><creator>Folmer, James J</creator><creator>Cacciola, Joseph</creator><creator>Scott, Clay</creator><creator>Lazor, Lois A</creator><creator>Pourashraf, Mehrnaz</creator><creator>Santhakumar, Vijayaratnam</creator><creator>Potts, William M</creator><creator>Sydserff, Simon</creator><creator>Giguère, Pascall</creator><creator>Lévesque, Carine</creator><creator>Dasser, Mohammed</creator><creator>Groblewski, Thierry</creator><general>American Chemical Society</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>20140213</creationdate><title>Discovery of Spirofused Piperazine and Diazepane Amides as Selective Histamine‑3 Antagonists with in Vivo Efficacy in a Mouse Model of Cognition</title><author>Brown, Dean G ; Bernstein, Peter R ; Griffin, Andrew ; Wesolowski, Steve ; Labrecque, Denis ; Tremblay, Maxime C ; Sylvester, Mark ; Mauger, Russell ; Edwards, Phillip D ; Throner, Scott R ; Folmer, James J ; Cacciola, Joseph ; Scott, Clay ; Lazor, Lois A ; Pourashraf, Mehrnaz ; Santhakumar, Vijayaratnam ; Potts, William M ; Sydserff, Simon ; Giguère, Pascall ; Lévesque, Carine ; Dasser, Mohammed ; Groblewski, Thierry</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a315t-d0ae10f943ba7b7d8039b2d0c5f6b9efc03bc9aae8674c0e6db76f3383214f893</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2014</creationdate><topic>Animals</topic><topic>Azetidines - chemical synthesis</topic><topic>Azetidines - pharmacokinetics</topic><topic>Azetidines - pharmacology</topic><topic>Cell Membrane Permeability</topic><topic>CHO Cells</topic><topic>Cognition - drug effects</topic><topic>Cricetinae</topic><topic>Cricetulus</topic><topic>Cyclopropanes - chemical synthesis</topic><topic>Cyclopropanes - pharmacokinetics</topic><topic>Cyclopropanes - pharmacology</topic><topic>Dogs</topic><topic>Histamine H3 Antagonists - chemical synthesis</topic><topic>Histamine H3 Antagonists - pharmacokinetics</topic><topic>Histamine H3 Antagonists - pharmacology</topic><topic>Humans</topic><topic>Learning - drug effects</topic><topic>Madin Darby Canine Kidney Cells</topic><topic>Male</topic><topic>Mice</topic><topic>Microsomes, Liver - metabolism</topic><topic>Models, Molecular</topic><topic>Piperazines - chemical synthesis</topic><topic>Piperazines - pharmacokinetics</topic><topic>Piperazines - pharmacology</topic><topic>Piperidines - chemical synthesis</topic><topic>Piperidines - pharmacokinetics</topic><topic>Piperidines - pharmacology</topic><topic>Pyrrolidines - chemical synthesis</topic><topic>Pyrrolidines - pharmacokinetics</topic><topic>Pyrrolidines - pharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Histamine H3 - genetics</topic><topic>Receptors, Histamine H3 - metabolism</topic><topic>Recognition (Psychology) - drug effects</topic><topic>Spiro Compounds - chemical synthesis</topic><topic>Spiro Compounds - pharmacokinetics</topic><topic>Spiro Compounds - pharmacology</topic><topic>Stereoisomerism</topic><topic>Structure-Activity Relationship</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Brown, Dean G</creatorcontrib><creatorcontrib>Bernstein, Peter R</creatorcontrib><creatorcontrib>Griffin, Andrew</creatorcontrib><creatorcontrib>Wesolowski, Steve</creatorcontrib><creatorcontrib>Labrecque, Denis</creatorcontrib><creatorcontrib>Tremblay, Maxime C</creatorcontrib><creatorcontrib>Sylvester, Mark</creatorcontrib><creatorcontrib>Mauger, Russell</creatorcontrib><creatorcontrib>Edwards, Phillip D</creatorcontrib><creatorcontrib>Throner, Scott R</creatorcontrib><creatorcontrib>Folmer, James J</creatorcontrib><creatorcontrib>Cacciola, Joseph</creatorcontrib><creatorcontrib>Scott, Clay</creatorcontrib><creatorcontrib>Lazor, Lois A</creatorcontrib><creatorcontrib>Pourashraf, Mehrnaz</creatorcontrib><creatorcontrib>Santhakumar, Vijayaratnam</creatorcontrib><creatorcontrib>Potts, William M</creatorcontrib><creatorcontrib>Sydserff, Simon</creatorcontrib><creatorcontrib>Giguère, Pascall</creatorcontrib><creatorcontrib>Lévesque, Carine</creatorcontrib><creatorcontrib>Dasser, Mohammed</creatorcontrib><creatorcontrib>Groblewski, Thierry</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>Journal of medicinal chemistry</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Brown, Dean G</au><au>Bernstein, Peter R</au><au>Griffin, Andrew</au><au>Wesolowski, Steve</au><au>Labrecque, Denis</au><au>Tremblay, Maxime C</au><au>Sylvester, Mark</au><au>Mauger, Russell</au><au>Edwards, Phillip D</au><au>Throner, Scott R</au><au>Folmer, James J</au><au>Cacciola, Joseph</au><au>Scott, Clay</au><au>Lazor, Lois A</au><au>Pourashraf, Mehrnaz</au><au>Santhakumar, Vijayaratnam</au><au>Potts, William M</au><au>Sydserff, Simon</au><au>Giguère, Pascall</au><au>Lévesque, Carine</au><au>Dasser, Mohammed</au><au>Groblewski, Thierry</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of Spirofused Piperazine and Diazepane Amides as Selective Histamine‑3 Antagonists with in Vivo Efficacy in a Mouse Model of Cognition</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2014-02-13</date><risdate>2014</risdate><volume>57</volume><issue>3</issue><spage>733</spage><epage>758</epage><pages>733-758</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>A new series of potent and selective histamine-3 receptor (H3R) antagonists was identified on the basis of an azaspiro[2.5]octane carboxamide scaffold. Many scaffold modifications were largely tolerated, resulting in nanomolar-potent compounds in the H3R functional assay. Exemplar compound 6s demonstrated a selective profile against a panel of 144 secondary pharmacological receptors, with activity at only σ2 (62% at 10 μM). Compound 6s demonstrated free-plasma exposures above the IC50 (∼50×) with a brain-to-plasma ratio of ∼3 following intravenous dosing in mice. At three doses tested in the mouse novel object recognition model (1, 3, and 10 mg/kg s.c.), 6s demonstrated a statistically significant response compared with the control group. This series represents a new scaffold of H3 receptor antagonists that demonstrates in vivo exposure and efficacy in an animal model of cognition.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>24410637</pmid><doi>10.1021/jm4014828</doi><tpages>26</tpages></addata></record> |
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| ispartof | Journal of medicinal chemistry, 2014-02, Vol.57 (3), p.733-758 |
| issn | 0022-2623 1520-4804 |
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| source | ACS Publications; MEDLINE |
| subjects | Animals Azetidines - chemical synthesis Azetidines - pharmacokinetics Azetidines - pharmacology Cell Membrane Permeability CHO Cells Cognition - drug effects Cricetinae Cricetulus Cyclopropanes - chemical synthesis Cyclopropanes - pharmacokinetics Cyclopropanes - pharmacology Dogs Histamine H3 Antagonists - chemical synthesis Histamine H3 Antagonists - pharmacokinetics Histamine H3 Antagonists - pharmacology Humans Learning - drug effects Madin Darby Canine Kidney Cells Male Mice Microsomes, Liver - metabolism Models, Molecular Piperazines - chemical synthesis Piperazines - pharmacokinetics Piperazines - pharmacology Piperidines - chemical synthesis Piperidines - pharmacokinetics Piperidines - pharmacology Pyrrolidines - chemical synthesis Pyrrolidines - pharmacokinetics Pyrrolidines - pharmacology Rats Rats, Sprague-Dawley Receptors, Histamine H3 - genetics Receptors, Histamine H3 - metabolism Recognition (Psychology) - drug effects Spiro Compounds - chemical synthesis Spiro Compounds - pharmacokinetics Spiro Compounds - pharmacology Stereoisomerism Structure-Activity Relationship |
| title | Discovery of Spirofused Piperazine and Diazepane Amides as Selective Histamine‑3 Antagonists with in Vivo Efficacy in a Mouse Model of Cognition |
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