Discovery of 3‑({5-Chloro-1-[3-(methylsulfonyl)propyl]‑1H‑indol-2-yl}methyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro‑2H‑imidazo[4,5‑c]pyridin-2-one (JNJ-53718678), a Potent and Orally Bioavailable Fusion Inhibitor of Respiratory Syncytial Virus
Respiratory syncytial virus (RSV) is a seasonal virus that infects the lungs and airways of 64 million children and adults every year. It is a major cause of acute lower respiratory tract infection and is associated with significant morbidity and mortality. Despite the large medical and economic bur...
Gespeichert in:
| Veröffentlicht in: | J. Med. Chem 2020-08, Vol.63 (15), p.8046-8058 |
|---|---|
| Hauptverfasser: | , , , , , , , , , , , , , |
| Format: | Artikel |
| Sprache: | eng |
| Online-Zugang: | Volltext |
| Tags: |
Tag hinzufügen
Keine Tags, Fügen Sie den ersten Tag hinzu!
|
| container_end_page | 8058 |
|---|---|
| container_issue | 15 |
| container_start_page | 8046 |
| container_title | J. Med. Chem |
| container_volume | 63 |
| creator | Vendeville, Sandrine Tahri, Abdellah Hu, Lili Demin, Samuel Cooymans, Ludwig Vos, Ann Kwanten, Leen Van den Berg, Joke Battles, Michael B McLellan, Jason S Koul, Anil Raboisson, Pierre Roymans, Dirk Jonckers, Tim H. M |
| description | Respiratory syncytial virus (RSV) is a seasonal virus that infects the lungs and airways of 64 million children and adults every year. It is a major cause of acute lower respiratory tract infection and is associated with significant morbidity and mortality. Despite the large medical and economic burden, treatment options for RSV-associated bronchiolitis and pneumonia are limited and mainly consist of supportive care. This publication covers the medicinal chemistry efforts resulting in the identification of JNJ-53718678, an orally bioavailable RSV inhibitor that was shown to be efficacious in a phase 2a challenge study in healthy adult subjects and that is currently being evaluated in hospitalized infants and adults. Cocrystal structures of several new derivatives helped in rationalizing some of the structure–activity relationship (SAR) trends observed. |
| doi_str_mv | 10.1021/acs.jmedchem.0c00226 |
| format | Article |
| fullrecord | <record><control><sourceid>proquest_osti_</sourceid><recordid>TN_cdi_proquest_miscellaneous_2404040148</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><sourcerecordid>2404040148</sourcerecordid><originalsourceid>FETCH-LOGICAL-a209t-1e5cbac9d2815172e8d2c211adeaab0a08a2d5b245981689667253c8fe387db83</originalsourceid><addsrcrecordid>eNo1ku1qFDEUhgdR7Fq9A5Hgr13YrPmYj-xPXa1tKVb8-lPKkEmyTJZMsiaZQhTBW_BCvAkvxRvRbHfLgYRz8pwXTs5bFE8xWmBE8AsuwmIzKCl6NSyQQIiQ-l4xwRVBsGSovF9MdjVIakKPikchbBBCFBP6sDiipEQNxtWk-PdaB-FulE_ArQH9-_PX9HsFV71x3kEMryicDir2yYTRrJ1NZrb1bpvMdSbxaT60lc5AApP5sQdnuW1K5jlg9Hptxqx09zCnUOo-Se9yJ7ltH7Tk39xVOa9yJq7__N4mr6W2WdJZBabn785hRRvM6obN5oCD9y4qGwG3Elx6bkwCr7TjN1wb3hkFTsagnQVnttedjs7vxvqgwlZ7nrMEPiYrUtTcgC_aj-Fx8WDNTVBPDvdx8fnkzafVKby4fHu2enkBOUHLCLGqRMfFUhKGK9wQxSQRBGMuFecd4ohxIquOlNWS4Zot67ohFRVsrShrZMfocfF8r-tC1G0QOirRC2etErHFdY0RKjM03UP5j7-OKsR2yNtRxnCr3BjavLVd4HKn9-yAjl02Qbv1euA-tXebzQDaA9kn7caN3ubxWozanXna2-LBPO3BPPQ_L5e-Yg</addsrcrecordid><sourcetype>Open Access Repository</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>2404040148</pqid></control><display><type>article</type><title>Discovery of 3‑({5-Chloro-1-[3-(methylsulfonyl)propyl]‑1H‑indol-2-yl}methyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro‑2H‑imidazo[4,5‑c]pyridin-2-one (JNJ-53718678), a Potent and Orally Bioavailable Fusion Inhibitor of Respiratory Syncytial Virus</title><source>American Chemical Society Journals</source><creator>Vendeville, Sandrine ; Tahri, Abdellah ; Hu, Lili ; Demin, Samuel ; Cooymans, Ludwig ; Vos, Ann ; Kwanten, Leen ; Van den Berg, Joke ; Battles, Michael B ; McLellan, Jason S ; Koul, Anil ; Raboisson, Pierre ; Roymans, Dirk ; Jonckers, Tim H. M</creator><creatorcontrib>Vendeville, Sandrine ; Tahri, Abdellah ; Hu, Lili ; Demin, Samuel ; Cooymans, Ludwig ; Vos, Ann ; Kwanten, Leen ; Van den Berg, Joke ; Battles, Michael B ; McLellan, Jason S ; Koul, Anil ; Raboisson, Pierre ; Roymans, Dirk ; Jonckers, Tim H. M ; Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><description>Respiratory syncytial virus (RSV) is a seasonal virus that infects the lungs and airways of 64 million children and adults every year. It is a major cause of acute lower respiratory tract infection and is associated with significant morbidity and mortality. Despite the large medical and economic burden, treatment options for RSV-associated bronchiolitis and pneumonia are limited and mainly consist of supportive care. This publication covers the medicinal chemistry efforts resulting in the identification of JNJ-53718678, an orally bioavailable RSV inhibitor that was shown to be efficacious in a phase 2a challenge study in healthy adult subjects and that is currently being evaluated in hospitalized infants and adults. Cocrystal structures of several new derivatives helped in rationalizing some of the structure–activity relationship (SAR) trends observed.</description><identifier>ISSN: 0022-2623</identifier><identifier>EISSN: 1520-4804</identifier><identifier>DOI: 10.1021/acs.jmedchem.0c00226</identifier><identifier>PMID: 32407115</identifier><language>eng</language><publisher>United States: American Chemical Society</publisher><ispartof>J. Med. Chem, 2020-08, Vol.63 (15), p.8046-8058</ispartof><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0003-3974-822X</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://pubs.acs.org/doi/pdf/10.1021/acs.jmedchem.0c00226$$EPDF$$P50$$Gacs$$H</linktopdf><linktohtml>$$Uhttps://pubs.acs.org/doi/10.1021/acs.jmedchem.0c00226$$EHTML$$P50$$Gacs$$H</linktohtml><link.rule.ids>315,781,785,886,27078,27926,27927,56740,56790</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32407115$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink><backlink>$$Uhttps://www.osti.gov/biblio/1661004$$D View this record in Osti.gov$$Hfree_for_read</backlink></links><search><creatorcontrib>Vendeville, Sandrine</creatorcontrib><creatorcontrib>Tahri, Abdellah</creatorcontrib><creatorcontrib>Hu, Lili</creatorcontrib><creatorcontrib>Demin, Samuel</creatorcontrib><creatorcontrib>Cooymans, Ludwig</creatorcontrib><creatorcontrib>Vos, Ann</creatorcontrib><creatorcontrib>Kwanten, Leen</creatorcontrib><creatorcontrib>Van den Berg, Joke</creatorcontrib><creatorcontrib>Battles, Michael B</creatorcontrib><creatorcontrib>McLellan, Jason S</creatorcontrib><creatorcontrib>Koul, Anil</creatorcontrib><creatorcontrib>Raboisson, Pierre</creatorcontrib><creatorcontrib>Roymans, Dirk</creatorcontrib><creatorcontrib>Jonckers, Tim H. M</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><title>Discovery of 3‑({5-Chloro-1-[3-(methylsulfonyl)propyl]‑1H‑indol-2-yl}methyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro‑2H‑imidazo[4,5‑c]pyridin-2-one (JNJ-53718678), a Potent and Orally Bioavailable Fusion Inhibitor of Respiratory Syncytial Virus</title><title>J. Med. Chem</title><addtitle>J. Med. Chem</addtitle><description>Respiratory syncytial virus (RSV) is a seasonal virus that infects the lungs and airways of 64 million children and adults every year. It is a major cause of acute lower respiratory tract infection and is associated with significant morbidity and mortality. Despite the large medical and economic burden, treatment options for RSV-associated bronchiolitis and pneumonia are limited and mainly consist of supportive care. This publication covers the medicinal chemistry efforts resulting in the identification of JNJ-53718678, an orally bioavailable RSV inhibitor that was shown to be efficacious in a phase 2a challenge study in healthy adult subjects and that is currently being evaluated in hospitalized infants and adults. Cocrystal structures of several new derivatives helped in rationalizing some of the structure–activity relationship (SAR) trends observed.</description><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><recordid>eNo1ku1qFDEUhgdR7Fq9A5Hgr13YrPmYj-xPXa1tKVb8-lPKkEmyTJZMsiaZQhTBW_BCvAkvxRvRbHfLgYRz8pwXTs5bFE8xWmBE8AsuwmIzKCl6NSyQQIiQ-l4xwRVBsGSovF9MdjVIakKPikchbBBCFBP6sDiipEQNxtWk-PdaB-FulE_ArQH9-_PX9HsFV71x3kEMryicDir2yYTRrJ1NZrb1bpvMdSbxaT60lc5AApP5sQdnuW1K5jlg9Hptxqx09zCnUOo-Se9yJ7ltH7Tk39xVOa9yJq7__N4mr6W2WdJZBabn785hRRvM6obN5oCD9y4qGwG3Elx6bkwCr7TjN1wb3hkFTsagnQVnttedjs7vxvqgwlZ7nrMEPiYrUtTcgC_aj-Fx8WDNTVBPDvdx8fnkzafVKby4fHu2enkBOUHLCLGqRMfFUhKGK9wQxSQRBGMuFecd4ohxIquOlNWS4Zot67ohFRVsrShrZMfocfF8r-tC1G0QOirRC2etErHFdY0RKjM03UP5j7-OKsR2yNtRxnCr3BjavLVd4HKn9-yAjl02Qbv1euA-tXebzQDaA9kn7caN3ubxWozanXna2-LBPO3BPPQ_L5e-Yg</recordid><startdate>20200813</startdate><enddate>20200813</enddate><creator>Vendeville, Sandrine</creator><creator>Tahri, Abdellah</creator><creator>Hu, Lili</creator><creator>Demin, Samuel</creator><creator>Cooymans, Ludwig</creator><creator>Vos, Ann</creator><creator>Kwanten, Leen</creator><creator>Van den Berg, Joke</creator><creator>Battles, Michael B</creator><creator>McLellan, Jason S</creator><creator>Koul, Anil</creator><creator>Raboisson, Pierre</creator><creator>Roymans, Dirk</creator><creator>Jonckers, Tim H. M</creator><general>American Chemical Society</general><scope>NPM</scope><scope>7X8</scope><scope>OTOTI</scope><orcidid>https://orcid.org/0000-0003-3974-822X</orcidid></search><sort><creationdate>20200813</creationdate><title>Discovery of 3‑({5-Chloro-1-[3-(methylsulfonyl)propyl]‑1H‑indol-2-yl}methyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro‑2H‑imidazo[4,5‑c]pyridin-2-one (JNJ-53718678), a Potent and Orally Bioavailable Fusion Inhibitor of Respiratory Syncytial Virus</title><author>Vendeville, Sandrine ; Tahri, Abdellah ; Hu, Lili ; Demin, Samuel ; Cooymans, Ludwig ; Vos, Ann ; Kwanten, Leen ; Van den Berg, Joke ; Battles, Michael B ; McLellan, Jason S ; Koul, Anil ; Raboisson, Pierre ; Roymans, Dirk ; Jonckers, Tim H. M</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-a209t-1e5cbac9d2815172e8d2c211adeaab0a08a2d5b245981689667253c8fe387db83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2020</creationdate><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Vendeville, Sandrine</creatorcontrib><creatorcontrib>Tahri, Abdellah</creatorcontrib><creatorcontrib>Hu, Lili</creatorcontrib><creatorcontrib>Demin, Samuel</creatorcontrib><creatorcontrib>Cooymans, Ludwig</creatorcontrib><creatorcontrib>Vos, Ann</creatorcontrib><creatorcontrib>Kwanten, Leen</creatorcontrib><creatorcontrib>Van den Berg, Joke</creatorcontrib><creatorcontrib>Battles, Michael B</creatorcontrib><creatorcontrib>McLellan, Jason S</creatorcontrib><creatorcontrib>Koul, Anil</creatorcontrib><creatorcontrib>Raboisson, Pierre</creatorcontrib><creatorcontrib>Roymans, Dirk</creatorcontrib><creatorcontrib>Jonckers, Tim H. M</creatorcontrib><creatorcontrib>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</creatorcontrib><collection>PubMed</collection><collection>MEDLINE - Academic</collection><collection>OSTI.GOV</collection><jtitle>J. Med. Chem</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Vendeville, Sandrine</au><au>Tahri, Abdellah</au><au>Hu, Lili</au><au>Demin, Samuel</au><au>Cooymans, Ludwig</au><au>Vos, Ann</au><au>Kwanten, Leen</au><au>Van den Berg, Joke</au><au>Battles, Michael B</au><au>McLellan, Jason S</au><au>Koul, Anil</au><au>Raboisson, Pierre</au><au>Roymans, Dirk</au><au>Jonckers, Tim H. M</au><aucorp>Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of 3‑({5-Chloro-1-[3-(methylsulfonyl)propyl]‑1H‑indol-2-yl}methyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro‑2H‑imidazo[4,5‑c]pyridin-2-one (JNJ-53718678), a Potent and Orally Bioavailable Fusion Inhibitor of Respiratory Syncytial Virus</atitle><jtitle>J. Med. Chem</jtitle><addtitle>J. Med. Chem</addtitle><date>2020-08-13</date><risdate>2020</risdate><volume>63</volume><issue>15</issue><spage>8046</spage><epage>8058</epage><pages>8046-8058</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Respiratory syncytial virus (RSV) is a seasonal virus that infects the lungs and airways of 64 million children and adults every year. It is a major cause of acute lower respiratory tract infection and is associated with significant morbidity and mortality. Despite the large medical and economic burden, treatment options for RSV-associated bronchiolitis and pneumonia are limited and mainly consist of supportive care. This publication covers the medicinal chemistry efforts resulting in the identification of JNJ-53718678, an orally bioavailable RSV inhibitor that was shown to be efficacious in a phase 2a challenge study in healthy adult subjects and that is currently being evaluated in hospitalized infants and adults. Cocrystal structures of several new derivatives helped in rationalizing some of the structure–activity relationship (SAR) trends observed.</abstract><cop>United States</cop><pub>American Chemical Society</pub><pmid>32407115</pmid><doi>10.1021/acs.jmedchem.0c00226</doi><tpages>13</tpages><orcidid>https://orcid.org/0000-0003-3974-822X</orcidid></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | J. Med. Chem, 2020-08, Vol.63 (15), p.8046-8058 |
| issn | 0022-2623 1520-4804 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_2404040148 |
| source | American Chemical Society Journals |
| title | Discovery of 3‑({5-Chloro-1-[3-(methylsulfonyl)propyl]‑1H‑indol-2-yl}methyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro‑2H‑imidazo[4,5‑c]pyridin-2-one (JNJ-53718678), a Potent and Orally Bioavailable Fusion Inhibitor of Respiratory Syncytial Virus |
| url | https://sfx.bib-bvb.de/sfx_tum?ctx_ver=Z39.88-2004&ctx_enc=info:ofi/enc:UTF-8&ctx_tim=2024-12-18T10%3A15%3A59IST&url_ver=Z39.88-2004&url_ctx_fmt=infofi/fmt:kev:mtx:ctx&rfr_id=info:sid/primo.exlibrisgroup.com:primo3-Article-proquest_osti_&rft_val_fmt=info:ofi/fmt:kev:mtx:journal&rft.genre=article&rft.atitle=Discovery%20of%203%E2%80%91(%7B5-Chloro-1-%5B3-(methylsulfonyl)propyl%5D%E2%80%911H%E2%80%91indol-2-yl%7Dmethyl)-1-(2,2,2-trifluoroethyl)-1,3-dihydro%E2%80%912H%E2%80%91imidazo%5B4,5%E2%80%91c%5D%C2%ADpyridin-2-one%20(JNJ-53718678),%20a%20Potent%20and%20Orally%20Bioavailable%20Fusion%20Inhibitor%20of%20Respiratory%20Syncytial%20Virus&rft.jtitle=J.%20Med.%20Chem&rft.au=Vendeville,%20Sandrine&rft.aucorp=Argonne%20National%20Lab.%20(ANL),%20Argonne,%20IL%20(United%20States).%20Advanced%20Photon%20Source%20(APS)&rft.date=2020-08-13&rft.volume=63&rft.issue=15&rft.spage=8046&rft.epage=8058&rft.pages=8046-8058&rft.issn=0022-2623&rft.eissn=1520-4804&rft_id=info:doi/10.1021/acs.jmedchem.0c00226&rft_dat=%3Cproquest_osti_%3E2404040148%3C/proquest_osti_%3E%3Curl%3E%3C/url%3E&disable_directlink=true&sfx.directlink=off&sfx.report_link=0&rft_id=info:oai/&rft_pqid=2404040148&rft_id=info:pmid/32407115&rfr_iscdi=true |