Discovery of (R)‑4-Cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro‑1H‑pyrazolo[4,3‑c]quinoline (ELND006) and (R)‑4-Cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro‑2H‑pyrazolo[4,3‑c]quinoline (ELND007): Metabolically Stable γ‑Secretase Inhibitors that Selectively Inhibit the Production of Amyloid‑β over Notch
Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aβ generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trial...
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| Veröffentlicht in: | Journal of medicinal chemistry 2013-07, Vol.56 (13), p.5261-5274 |
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| container_end_page | 5274 |
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| container_issue | 13 |
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| container_title | Journal of medicinal chemistry |
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| creator | Probst, Gary Aubele, Danielle L Bowers, Simeon Dressen, Darren Garofalo, Albert W Hom, Roy K Konradi, Andrei W Marugg, Jennifer L Mattson, Matthew N Neitzel, Martin L Semko, Chris M Sham, Hing L Smith, Jenifer Sun, Minghua Truong, Anh P Ye, Xiaocong M Xu, Ying-zi Dappen, Michael S Jagodzinski, Jacek J Keim, Pamela S Peterson, Brian Latimer, Lee H Quincy, David Wu, Jing Goldbach, Erich Ness, Daniel K Quinn, Kevin P Sauer, John-Michael Wong, Karina Zhang, Hongbin Zmolek, Wes Brigham, Elizabeth F Kholodenko, Dora Hu, Kang Kwong, Grace T Lee, Michael Liao, Anna Motter, Ruth N Sacayon, Patricia Santiago, Pamela Willits, Christopher Bard, Frédérique Bova, Michael P Hemphill, Susanna S Nguyen, Lam Ruslim, Lany Tanaka, Kevin Tanaka, Pearl Wallace, William Yednock, Ted A Basi, Guriqbal S |
| description | Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aβ generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aβ generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aβ in the CSF of healthy human volunteers. |
| doi_str_mv | 10.1021/jm301741t |
| format | Article |
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We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aβ generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aβ in the CSF of healthy human volunteers.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/jm301741t</identifier><identifier>PMID: 23713656</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><subject>Amyloid beta-Peptides - antagonists & inhibitors ; Amyloid beta-Peptides - cerebrospinal fluid ; Amyloid beta-Peptides - metabolism ; Amyloid Precursor Protein Secretases - antagonists & inhibitors ; Amyloid Precursor Protein Secretases - metabolism ; Animals ; Area Under Curve ; Basic Helix-Loop-Helix Transcription Factors - genetics ; Dogs ; Dose-Response Relationship, Drug ; Drug Design ; Drug Stability ; Enzyme Inhibitors - chemical synthesis ; Enzyme Inhibitors - pharmacokinetics ; Enzyme Inhibitors - pharmacology ; Gene Expression - drug effects ; Heterocyclic Compounds, 3-Ring - chemistry ; Heterocyclic Compounds, 3-Ring - pharmacology ; Homeodomain Proteins - genetics ; Humans ; Male ; Mice ; Microsomes, Liver - drug effects ; Microsomes, Liver - metabolism ; Models, Chemical ; Molecular Structure ; Pyrazoles - chemical synthesis ; Pyrazoles - pharmacokinetics ; Pyrazoles - pharmacology ; Quinolines - chemical synthesis ; Quinolines - pharmacokinetics ; Quinolines - pharmacology ; Rats ; Rats, Sprague-Dawley ; Receptors, Notch - antagonists & inhibitors ; Receptors, Notch - metabolism ; RNA, Messenger - genetics ; RNA, Messenger - metabolism ; Structure-Activity Relationship ; Sulfonamides - chemistry ; Sulfonamides - pharmacology ; Time Factors ; Transcription Factor HES-1</subject><ispartof>Journal of medicinal chemistry, 2013-07, Vol.56 (13), p.5261-5274</ispartof><rights>Copyright © 2013 American Chemical Society</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/jm301741t$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/jm301741t$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>314,776,780,27053,27901,27902,56713,56763</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/23713656$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Probst, Gary</creatorcontrib><creatorcontrib>Aubele, Danielle L</creatorcontrib><creatorcontrib>Bowers, Simeon</creatorcontrib><creatorcontrib>Dressen, Darren</creatorcontrib><creatorcontrib>Garofalo, Albert W</creatorcontrib><creatorcontrib>Hom, Roy K</creatorcontrib><creatorcontrib>Konradi, Andrei W</creatorcontrib><creatorcontrib>Marugg, Jennifer L</creatorcontrib><creatorcontrib>Mattson, Matthew N</creatorcontrib><creatorcontrib>Neitzel, Martin L</creatorcontrib><creatorcontrib>Semko, Chris M</creatorcontrib><creatorcontrib>Sham, Hing L</creatorcontrib><creatorcontrib>Smith, Jenifer</creatorcontrib><creatorcontrib>Sun, Minghua</creatorcontrib><creatorcontrib>Truong, Anh P</creatorcontrib><creatorcontrib>Ye, Xiaocong M</creatorcontrib><creatorcontrib>Xu, Ying-zi</creatorcontrib><creatorcontrib>Dappen, Michael S</creatorcontrib><creatorcontrib>Jagodzinski, Jacek J</creatorcontrib><creatorcontrib>Keim, Pamela S</creatorcontrib><creatorcontrib>Peterson, Brian</creatorcontrib><creatorcontrib>Latimer, Lee H</creatorcontrib><creatorcontrib>Quincy, David</creatorcontrib><creatorcontrib>Wu, Jing</creatorcontrib><creatorcontrib>Goldbach, Erich</creatorcontrib><creatorcontrib>Ness, Daniel K</creatorcontrib><creatorcontrib>Quinn, Kevin P</creatorcontrib><creatorcontrib>Sauer, John-Michael</creatorcontrib><creatorcontrib>Wong, Karina</creatorcontrib><creatorcontrib>Zhang, Hongbin</creatorcontrib><creatorcontrib>Zmolek, Wes</creatorcontrib><creatorcontrib>Brigham, Elizabeth F</creatorcontrib><creatorcontrib>Kholodenko, Dora</creatorcontrib><creatorcontrib>Hu, Kang</creatorcontrib><creatorcontrib>Kwong, Grace T</creatorcontrib><creatorcontrib>Lee, Michael</creatorcontrib><creatorcontrib>Liao, Anna</creatorcontrib><creatorcontrib>Motter, Ruth N</creatorcontrib><creatorcontrib>Sacayon, Patricia</creatorcontrib><creatorcontrib>Santiago, Pamela</creatorcontrib><creatorcontrib>Willits, Christopher</creatorcontrib><creatorcontrib>Bard, Frédérique</creatorcontrib><creatorcontrib>Bova, Michael P</creatorcontrib><creatorcontrib>Hemphill, Susanna S</creatorcontrib><creatorcontrib>Nguyen, Lam</creatorcontrib><creatorcontrib>Ruslim, Lany</creatorcontrib><creatorcontrib>Tanaka, Kevin</creatorcontrib><creatorcontrib>Tanaka, Pearl</creatorcontrib><creatorcontrib>Wallace, William</creatorcontrib><creatorcontrib>Yednock, Ted A</creatorcontrib><creatorcontrib>Basi, Guriqbal S</creatorcontrib><title>Discovery of (R)‑4-Cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro‑1H‑pyrazolo[4,3‑c]quinoline (ELND006) and (R)‑4-Cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro‑2H‑pyrazolo[4,3‑c]quinoline (ELND007): Metabolically Stable γ‑Secretase Inhibitors that Selectively Inhibit the Production of Amyloid‑β over Notch</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. Chem</addtitle><description>Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aβ generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aβ generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aβ in the CSF of healthy human volunteers.</description><subject>Amyloid beta-Peptides - antagonists & inhibitors</subject><subject>Amyloid beta-Peptides - cerebrospinal fluid</subject><subject>Amyloid beta-Peptides - metabolism</subject><subject>Amyloid Precursor Protein Secretases - antagonists & inhibitors</subject><subject>Amyloid Precursor Protein Secretases - metabolism</subject><subject>Animals</subject><subject>Area Under Curve</subject><subject>Basic Helix-Loop-Helix Transcription Factors - genetics</subject><subject>Dogs</subject><subject>Dose-Response Relationship, Drug</subject><subject>Drug Design</subject><subject>Drug Stability</subject><subject>Enzyme Inhibitors - chemical synthesis</subject><subject>Enzyme Inhibitors - pharmacokinetics</subject><subject>Enzyme Inhibitors - pharmacology</subject><subject>Gene Expression - drug effects</subject><subject>Heterocyclic Compounds, 3-Ring - chemistry</subject><subject>Heterocyclic Compounds, 3-Ring - pharmacology</subject><subject>Homeodomain Proteins - genetics</subject><subject>Humans</subject><subject>Male</subject><subject>Mice</subject><subject>Microsomes, Liver - drug effects</subject><subject>Microsomes, Liver - metabolism</subject><subject>Models, Chemical</subject><subject>Molecular Structure</subject><subject>Pyrazoles - chemical synthesis</subject><subject>Pyrazoles - pharmacokinetics</subject><subject>Pyrazoles - pharmacology</subject><subject>Quinolines - chemical synthesis</subject><subject>Quinolines - pharmacokinetics</subject><subject>Quinolines - pharmacology</subject><subject>Rats</subject><subject>Rats, Sprague-Dawley</subject><subject>Receptors, Notch - antagonists & inhibitors</subject><subject>Receptors, Notch - metabolism</subject><subject>RNA, Messenger - genetics</subject><subject>RNA, Messenger - metabolism</subject><subject>Structure-Activity Relationship</subject><subject>Sulfonamides - chemistry</subject><subject>Sulfonamides - pharmacology</subject><subject>Time Factors</subject><subject>Transcription Factor HES-1</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2013</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqNUs1u1DAQDghEl8KBF0C-IO1Ka_BfnGxv1bbQSktBLJwQihzbUbxy4q3jVDInJJ6AV4H36EPwJHjVBS5F4uLRzPfNN5_Gk2VPMHqOEcEvNh1FuGA43M0mOCcIshKxe9kEIUIg4YQeZA-HYYMQopjQB9kBoQWmPOeTO19PzCDdlfYRuAZM381-fvnG4DJK67bebaOFxbyEyjR2dN7BHE4ZnAa_zzsd2mhn21b30Q6jbVyKM8jmeWppo_IuyeGz9GyjF5-ddR_ZnKZUfrocTe-s6TWYnq4uThDiMyB6dauFEv4dz28ZH71RpocU_tsE-T8TxewIvNZB1KkqhbURrFNiNbj-kRrWWvoEDhqc962pTXB-AKEVAay11TKYK5069lgCNHjrnRoT4Prdeo-7aJ1RSen6O9gtHVy4INtH2f1G2EE_3sfD7MPL0_fLM7h68-p8ebyCAhc4QMxUgzUqa8VrLYngIsdSsoUqOCsWuliwomSU0lLUmJFFI0Ujcl5zoRLAaUkPs-mNblrr5aiHUHXp87W1otduHCrMFqjIOScoUZ_uqWPdaVVtvemEj9Xvw0mEZzcEIYdq40bfJ-cVRtXuIKs_B0l_AT9U30g</recordid><startdate>20130711</startdate><enddate>20130711</enddate><creator>Probst, Gary</creator><creator>Aubele, Danielle L</creator><creator>Bowers, Simeon</creator><creator>Dressen, Darren</creator><creator>Garofalo, Albert W</creator><creator>Hom, Roy K</creator><creator>Konradi, Andrei W</creator><creator>Marugg, Jennifer L</creator><creator>Mattson, Matthew N</creator><creator>Neitzel, Martin L</creator><creator>Semko, Chris M</creator><creator>Sham, Hing L</creator><creator>Smith, Jenifer</creator><creator>Sun, Minghua</creator><creator>Truong, Anh P</creator><creator>Ye, Xiaocong M</creator><creator>Xu, Ying-zi</creator><creator>Dappen, Michael S</creator><creator>Jagodzinski, Jacek J</creator><creator>Keim, Pamela S</creator><creator>Peterson, Brian</creator><creator>Latimer, Lee H</creator><creator>Quincy, David</creator><creator>Wu, Jing</creator><creator>Goldbach, Erich</creator><creator>Ness, Daniel K</creator><creator>Quinn, Kevin P</creator><creator>Sauer, John-Michael</creator><creator>Wong, Karina</creator><creator>Zhang, Hongbin</creator><creator>Zmolek, Wes</creator><creator>Brigham, Elizabeth F</creator><creator>Kholodenko, Dora</creator><creator>Hu, Kang</creator><creator>Kwong, Grace T</creator><creator>Lee, Michael</creator><creator>Liao, Anna</creator><creator>Motter, Ruth N</creator><creator>Sacayon, Patricia</creator><creator>Santiago, Pamela</creator><creator>Willits, Christopher</creator><creator>Bard, Frédérique</creator><creator>Bova, Michael P</creator><creator>Hemphill, Susanna S</creator><creator>Nguyen, Lam</creator><creator>Ruslim, Lany</creator><creator>Tanaka, Kevin</creator><creator>Tanaka, Pearl</creator><creator>Wallace, William</creator><creator>Yednock, Ted A</creator><creator>Basi, Guriqbal S</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>7X8</scope></search><sort><creationdate>20130711</creationdate><title>Discovery of (R)‑4-Cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro‑1H‑pyrazolo[4,3‑c]quinoline (ELND006) and (R)‑4-Cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro‑2H‑pyrazolo[4,3‑c]quinoline (ELND007): Metabolically Stable γ‑Secretase Inhibitors that Selectively Inhibit the Production of Amyloid‑β over Notch</title><author>Probst, Gary ; Aubele, Danielle L ; Bowers, Simeon ; Dressen, Darren ; Garofalo, Albert W ; Hom, Roy K ; Konradi, Andrei W ; Marugg, Jennifer L ; Mattson, Matthew N ; Neitzel, Martin L ; Semko, Chris M ; Sham, Hing L ; Smith, Jenifer ; Sun, Minghua ; Truong, Anh P ; Ye, Xiaocong M ; Xu, Ying-zi ; Dappen, Michael S ; Jagodzinski, Jacek J ; Keim, Pamela S ; Peterson, Brian ; Latimer, Lee H ; Quincy, David ; Wu, Jing ; Goldbach, Erich ; Ness, Daniel K ; Quinn, Kevin P ; Sauer, John-Michael ; Wong, Karina ; Zhang, Hongbin ; Zmolek, Wes ; Brigham, Elizabeth F ; Kholodenko, Dora ; Hu, Kang ; Kwong, Grace T ; Lee, Michael ; Liao, Anna ; Motter, Ruth N ; Sacayon, Patricia ; Santiago, Pamela ; Willits, Christopher ; Bard, Frédérique ; Bova, Michael P ; Hemphill, Susanna S ; Nguyen, Lam ; Ruslim, Lany ; Tanaka, Kevin ; Tanaka, Pearl ; Wallace, William ; Yednock, Ted A ; Basi, Guriqbal S</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a171t-14df1e08bd6bec2a6a51cc49d76479e7947843338ab1429fcafa56b6ad4786383</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2013</creationdate><topic>Amyloid beta-Peptides - antagonists & inhibitors</topic><topic>Amyloid beta-Peptides - cerebrospinal fluid</topic><topic>Amyloid beta-Peptides - metabolism</topic><topic>Amyloid Precursor Protein Secretases - antagonists & inhibitors</topic><topic>Amyloid Precursor Protein Secretases - metabolism</topic><topic>Animals</topic><topic>Area Under Curve</topic><topic>Basic Helix-Loop-Helix Transcription Factors - genetics</topic><topic>Dogs</topic><topic>Dose-Response Relationship, Drug</topic><topic>Drug Design</topic><topic>Drug Stability</topic><topic>Enzyme Inhibitors - chemical synthesis</topic><topic>Enzyme Inhibitors - pharmacokinetics</topic><topic>Enzyme Inhibitors - pharmacology</topic><topic>Gene Expression - drug effects</topic><topic>Heterocyclic Compounds, 3-Ring - chemistry</topic><topic>Heterocyclic Compounds, 3-Ring - pharmacology</topic><topic>Homeodomain Proteins - genetics</topic><topic>Humans</topic><topic>Male</topic><topic>Mice</topic><topic>Microsomes, Liver - drug effects</topic><topic>Microsomes, Liver - metabolism</topic><topic>Models, Chemical</topic><topic>Molecular Structure</topic><topic>Pyrazoles - chemical synthesis</topic><topic>Pyrazoles - pharmacokinetics</topic><topic>Pyrazoles - pharmacology</topic><topic>Quinolines - chemical synthesis</topic><topic>Quinolines - pharmacokinetics</topic><topic>Quinolines - pharmacology</topic><topic>Rats</topic><topic>Rats, Sprague-Dawley</topic><topic>Receptors, Notch - antagonists & inhibitors</topic><topic>Receptors, Notch - metabolism</topic><topic>RNA, Messenger - genetics</topic><topic>RNA, Messenger - metabolism</topic><topic>Structure-Activity Relationship</topic><topic>Sulfonamides - chemistry</topic><topic>Sulfonamides - pharmacology</topic><topic>Time Factors</topic><topic>Transcription Factor HES-1</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Probst, Gary</creatorcontrib><creatorcontrib>Aubele, Danielle L</creatorcontrib><creatorcontrib>Bowers, Simeon</creatorcontrib><creatorcontrib>Dressen, Darren</creatorcontrib><creatorcontrib>Garofalo, Albert W</creatorcontrib><creatorcontrib>Hom, Roy K</creatorcontrib><creatorcontrib>Konradi, Andrei W</creatorcontrib><creatorcontrib>Marugg, Jennifer L</creatorcontrib><creatorcontrib>Mattson, Matthew N</creatorcontrib><creatorcontrib>Neitzel, Martin L</creatorcontrib><creatorcontrib>Semko, Chris M</creatorcontrib><creatorcontrib>Sham, Hing L</creatorcontrib><creatorcontrib>Smith, Jenifer</creatorcontrib><creatorcontrib>Sun, Minghua</creatorcontrib><creatorcontrib>Truong, Anh P</creatorcontrib><creatorcontrib>Ye, Xiaocong M</creatorcontrib><creatorcontrib>Xu, Ying-zi</creatorcontrib><creatorcontrib>Dappen, Michael S</creatorcontrib><creatorcontrib>Jagodzinski, Jacek J</creatorcontrib><creatorcontrib>Keim, Pamela S</creatorcontrib><creatorcontrib>Peterson, Brian</creatorcontrib><creatorcontrib>Latimer, Lee H</creatorcontrib><creatorcontrib>Quincy, David</creatorcontrib><creatorcontrib>Wu, Jing</creatorcontrib><creatorcontrib>Goldbach, Erich</creatorcontrib><creatorcontrib>Ness, Daniel K</creatorcontrib><creatorcontrib>Quinn, Kevin P</creatorcontrib><creatorcontrib>Sauer, John-Michael</creatorcontrib><creatorcontrib>Wong, Karina</creatorcontrib><creatorcontrib>Zhang, Hongbin</creatorcontrib><creatorcontrib>Zmolek, Wes</creatorcontrib><creatorcontrib>Brigham, Elizabeth F</creatorcontrib><creatorcontrib>Kholodenko, Dora</creatorcontrib><creatorcontrib>Hu, Kang</creatorcontrib><creatorcontrib>Kwong, Grace T</creatorcontrib><creatorcontrib>Lee, Michael</creatorcontrib><creatorcontrib>Liao, Anna</creatorcontrib><creatorcontrib>Motter, Ruth N</creatorcontrib><creatorcontrib>Sacayon, Patricia</creatorcontrib><creatorcontrib>Santiago, Pamela</creatorcontrib><creatorcontrib>Willits, Christopher</creatorcontrib><creatorcontrib>Bard, Frédérique</creatorcontrib><creatorcontrib>Bova, Michael P</creatorcontrib><creatorcontrib>Hemphill, Susanna S</creatorcontrib><creatorcontrib>Nguyen, Lam</creatorcontrib><creatorcontrib>Ruslim, Lany</creatorcontrib><creatorcontrib>Tanaka, Kevin</creatorcontrib><creatorcontrib>Tanaka, Pearl</creatorcontrib><creatorcontrib>Wallace, William</creatorcontrib><creatorcontrib>Yednock, Ted A</creatorcontrib><creatorcontrib>Basi, Guriqbal S</creatorcontrib><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>Probst, Gary</au><au>Aubele, Danielle L</au><au>Bowers, Simeon</au><au>Dressen, Darren</au><au>Garofalo, Albert W</au><au>Hom, Roy K</au><au>Konradi, Andrei W</au><au>Marugg, Jennifer L</au><au>Mattson, Matthew N</au><au>Neitzel, Martin L</au><au>Semko, Chris M</au><au>Sham, Hing L</au><au>Smith, Jenifer</au><au>Sun, Minghua</au><au>Truong, Anh P</au><au>Ye, Xiaocong M</au><au>Xu, Ying-zi</au><au>Dappen, Michael S</au><au>Jagodzinski, Jacek J</au><au>Keim, Pamela S</au><au>Peterson, Brian</au><au>Latimer, Lee H</au><au>Quincy, David</au><au>Wu, Jing</au><au>Goldbach, Erich</au><au>Ness, Daniel K</au><au>Quinn, Kevin P</au><au>Sauer, John-Michael</au><au>Wong, Karina</au><au>Zhang, Hongbin</au><au>Zmolek, Wes</au><au>Brigham, Elizabeth F</au><au>Kholodenko, Dora</au><au>Hu, Kang</au><au>Kwong, Grace T</au><au>Lee, Michael</au><au>Liao, Anna</au><au>Motter, Ruth N</au><au>Sacayon, Patricia</au><au>Santiago, Pamela</au><au>Willits, Christopher</au><au>Bard, Frédérique</au><au>Bova, Michael P</au><au>Hemphill, Susanna S</au><au>Nguyen, Lam</au><au>Ruslim, Lany</au><au>Tanaka, Kevin</au><au>Tanaka, Pearl</au><au>Wallace, William</au><au>Yednock, Ted A</au><au>Basi, Guriqbal S</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of (R)‑4-Cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro‑1H‑pyrazolo[4,3‑c]quinoline (ELND006) and (R)‑4-Cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro‑2H‑pyrazolo[4,3‑c]quinoline (ELND007): Metabolically Stable γ‑Secretase Inhibitors that Selectively Inhibit the Production of Amyloid‑β over Notch</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2013-07-11</date><risdate>2013</risdate><volume>56</volume><issue>13</issue><spage>5261</spage><epage>5274</epage><pages>5261-5274</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Herein, we describe our strategy to design metabolically stable γ-secretase inhibitors which are selective for inhibition of Aβ generation over Notch. We highlight our synthetic strategy to incorporate diversity and chirality. Compounds 30 (ELND006) and 34 (ELND007) both entered human clinical trials. The in vitro and in vivo characteristics for these two compounds are described. A comparison of inhibition of Aβ generation in vivo between 30, 34, Semagacestat 41, Begacestat 42, and Avagacestat 43 in mice is made. 30 lowered Aβ in the CSF of healthy human volunteers.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>23713656</pmid><doi>10.1021/jm301741t</doi><tpages>14</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2013-07, Vol.56 (13), p.5261-5274 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_1490756620 |
| source | MEDLINE; American Chemical Society Journals |
| subjects | Amyloid beta-Peptides - antagonists & inhibitors Amyloid beta-Peptides - cerebrospinal fluid Amyloid beta-Peptides - metabolism Amyloid Precursor Protein Secretases - antagonists & inhibitors Amyloid Precursor Protein Secretases - metabolism Animals Area Under Curve Basic Helix-Loop-Helix Transcription Factors - genetics Dogs Dose-Response Relationship, Drug Drug Design Drug Stability Enzyme Inhibitors - chemical synthesis Enzyme Inhibitors - pharmacokinetics Enzyme Inhibitors - pharmacology Gene Expression - drug effects Heterocyclic Compounds, 3-Ring - chemistry Heterocyclic Compounds, 3-Ring - pharmacology Homeodomain Proteins - genetics Humans Male Mice Microsomes, Liver - drug effects Microsomes, Liver - metabolism Models, Chemical Molecular Structure Pyrazoles - chemical synthesis Pyrazoles - pharmacokinetics Pyrazoles - pharmacology Quinolines - chemical synthesis Quinolines - pharmacokinetics Quinolines - pharmacology Rats Rats, Sprague-Dawley Receptors, Notch - antagonists & inhibitors Receptors, Notch - metabolism RNA, Messenger - genetics RNA, Messenger - metabolism Structure-Activity Relationship Sulfonamides - chemistry Sulfonamides - pharmacology Time Factors Transcription Factor HES-1 |
| title | Discovery of (R)‑4-Cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro‑1H‑pyrazolo[4,3‑c]quinoline (ELND006) and (R)‑4-Cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro‑2H‑pyrazolo[4,3‑c]quinoline (ELND007): Metabolically Stable γ‑Secretase Inhibitors that Selectively Inhibit the Production of Amyloid‑β over Notch |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2025-02-11T12%3A05%3A03IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_pubme&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Discovery%20of%20(R)%E2%80%914-Cyclopropyl-7,8-difluoro-5-(4-(trifluoromethyl)phenylsulfonyl)-4,5-dihydro%E2%80%911H%E2%80%91pyrazolo%5B4,3%E2%80%91c%5Dquinoline%20(ELND006)%20and%20(R)%E2%80%914-Cyclopropyl-8-fluoro-5-(6-(trifluoromethyl)pyridin-3-ylsulfonyl)-4,5-dihydro%E2%80%912H%E2%80%91pyrazolo%5B4,3%E2%80%91c%5Dquinoline%20(ELND007):%20Metabolically%20Stable%20%CE%B3%E2%80%91Secretase%20Inhibitors%20that%20Selectively%20Inhibit%20the%20Production%20of%20Amyloid%E2%80%91%CE%B2%20over%20Notch&rft.jtitle=Journal%20of%20medicinal%20chemistry&rft.au=Probst,%20Gary&rft.date=2013-07-11&rft.volume=56&rft.issue=13&rft.spage=5261&rft.epage=5274&rft.pages=5261-5274&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/jm301741t&rft_dat=%3Cproquest_pubme%3E1490756620%3C/proquest_pubme%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=1490756620&rft_id=info:pmid/23713656&rfr_iscdi=true |