Discovery of JNJ-1802, a First-in-Class Pan-Serotype Dengue Virus NS4B Inhibitor
Dengue is a global public health threat, with about half of the world’s population at risk of contracting this mosquito-borne viral disease. Climate change, urbanization, and global travel accelerate the spread of dengue virus (DENV) to new areas, including southern parts of Europe and the US. Curre...
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| Veröffentlicht in: | Journal of medicinal chemistry 2024-03, Vol.67 (5), p.4063-4082 |
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| creator | Kesteleyn, Bart Bonfanti, Jean-François Bardiot, Dorothée De Boeck, Benoît Goethals, Olivia Kaptein, Suzanne J. F. Stoops, Bart Coesemans, Erwin Fortin, Jérôme Muller, Philippe Doublet, Frédéric Carlens, Gunter Koukni, Mohamed Smets, Wim Raboisson, Pierre Chaltin, Patrick Simmen, Kenny Loock, Marnix Van Neyts, Johan Marchand, Arnaud Jonckers, Tim H. M. |
| description | Dengue is a global public health threat, with about half of the world’s population at risk of contracting this mosquito-borne viral disease. Climate change, urbanization, and global travel accelerate the spread of dengue virus (DENV) to new areas, including southern parts of Europe and the US. Currently, no dengue-specific small-molecule antiviral for prophylaxis or treatment is available. Here, we report the discovery of JNJ-1802 as a potent, pan-serotype DENV inhibitor (EC50’s ranging from 0.057 to 11 nM against the four DENV serotypes). The observed oral bioavailability of JNJ-1802 across preclinical species, its low clearance in human hepatocytes, the absence of major in vitro pharmacology safety alerts, and a dose-proportional increase in efficacy against DENV-2 infection in mice were all supportive of its selection as a development candidate against dengue. JNJ-1802 is being progressed in clinical studies for the prevention or treatment of dengue. |
| doi_str_mv | 10.1021/acs.jmedchem.3c02336 |
| format | Article |
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F. ; Stoops, Bart ; Coesemans, Erwin ; Fortin, Jérôme ; Muller, Philippe ; Doublet, Frédéric ; Carlens, Gunter ; Koukni, Mohamed ; Smets, Wim ; Raboisson, Pierre ; Chaltin, Patrick ; Simmen, Kenny ; Loock, Marnix Van ; Neyts, Johan ; Marchand, Arnaud ; Jonckers, Tim H. M.</creator><creatorcontrib>Kesteleyn, Bart ; Bonfanti, Jean-François ; Bardiot, Dorothée ; De Boeck, Benoît ; Goethals, Olivia ; Kaptein, Suzanne J. F. ; Stoops, Bart ; Coesemans, Erwin ; Fortin, Jérôme ; Muller, Philippe ; Doublet, Frédéric ; Carlens, Gunter ; Koukni, Mohamed ; Smets, Wim ; Raboisson, Pierre ; Chaltin, Patrick ; Simmen, Kenny ; Loock, Marnix Van ; Neyts, Johan ; Marchand, Arnaud ; Jonckers, Tim H. M.</creatorcontrib><description>Dengue is a global public health threat, with about half of the world’s population at risk of contracting this mosquito-borne viral disease. Climate change, urbanization, and global travel accelerate the spread of dengue virus (DENV) to new areas, including southern parts of Europe and the US. Currently, no dengue-specific small-molecule antiviral for prophylaxis or treatment is available. Here, we report the discovery of JNJ-1802 as a potent, pan-serotype DENV inhibitor (EC50’s ranging from 0.057 to 11 nM against the four DENV serotypes). The observed oral bioavailability of JNJ-1802 across preclinical species, its low clearance in human hepatocytes, the absence of major in vitro pharmacology safety alerts, and a dose-proportional increase in efficacy against DENV-2 infection in mice were all supportive of its selection as a development candidate against dengue. 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F.</creatorcontrib><creatorcontrib>Stoops, Bart</creatorcontrib><creatorcontrib>Coesemans, Erwin</creatorcontrib><creatorcontrib>Fortin, Jérôme</creatorcontrib><creatorcontrib>Muller, Philippe</creatorcontrib><creatorcontrib>Doublet, Frédéric</creatorcontrib><creatorcontrib>Carlens, Gunter</creatorcontrib><creatorcontrib>Koukni, Mohamed</creatorcontrib><creatorcontrib>Smets, Wim</creatorcontrib><creatorcontrib>Raboisson, Pierre</creatorcontrib><creatorcontrib>Chaltin, Patrick</creatorcontrib><creatorcontrib>Simmen, Kenny</creatorcontrib><creatorcontrib>Loock, Marnix Van</creatorcontrib><creatorcontrib>Neyts, Johan</creatorcontrib><creatorcontrib>Marchand, Arnaud</creatorcontrib><creatorcontrib>Jonckers, Tim H. M.</creatorcontrib><title>Discovery of JNJ-1802, a First-in-Class Pan-Serotype Dengue Virus NS4B Inhibitor</title><title>Journal of medicinal chemistry</title><addtitle>J. Med. 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JNJ-1802 is being progressed in clinical studies for the prevention or treatment of dengue.</description><subject>Animals</subject><subject>Dengue - drug therapy</subject><subject>Dengue Virus</subject><subject>Humans</subject><subject>Hydrocarbons, Halogenated</subject><subject>Indoles</subject><subject>Mice</subject><subject>Serogroup</subject><issn>0022-2623</issn><issn>1520-4804</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kEtPwzAQhC0EouXxDxDykQMu63USO0cobyFAKnCNHGdDU7VJsROk_nsCLRw57Uo7M6v5GDuSMJKA8sy6MJotqHBTWoyUA1Qq2WJDGSOIyEC0zYYAiAITVAO2F8IMAJREtcsGykQGDeohe76sgms-ya94U_L7x3shDeApt_y68qEVVS3GcxsCf7a1mJBv2tWS-CXV7x3xt8p3gT9Oogt-V0-rvGobf8B2SjsPdLiZ--z1-uplfCsenm7uxucPwqrItKIgSHShHOYGc0oT6wzlRZHmaaktYJq6uCwIdeQKCTo1KnXKYr9pDYUBUvvsZJ279M1HR6HNFn0Tms9tTU0XMkxjLZNY6biXRmup800Insps6auF9atMQvbNMutZZr8ssw3L3na8-dDl_e3P9AuvF8Ba8GNvOl_3hf_P_AJB0YE6</recordid><startdate>20240314</startdate><enddate>20240314</enddate><creator>Kesteleyn, Bart</creator><creator>Bonfanti, Jean-François</creator><creator>Bardiot, Dorothée</creator><creator>De Boeck, Benoît</creator><creator>Goethals, Olivia</creator><creator>Kaptein, Suzanne J. 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M.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Discovery of JNJ-1802, a First-in-Class Pan-Serotype Dengue Virus NS4B Inhibitor</atitle><jtitle>Journal of medicinal chemistry</jtitle><addtitle>J. Med. Chem</addtitle><date>2024-03-14</date><risdate>2024</risdate><volume>67</volume><issue>5</issue><spage>4063</spage><epage>4082</epage><pages>4063-4082</pages><issn>0022-2623</issn><eissn>1520-4804</eissn><abstract>Dengue is a global public health threat, with about half of the world’s population at risk of contracting this mosquito-borne viral disease. Climate change, urbanization, and global travel accelerate the spread of dengue virus (DENV) to new areas, including southern parts of Europe and the US. Currently, no dengue-specific small-molecule antiviral for prophylaxis or treatment is available. Here, we report the discovery of JNJ-1802 as a potent, pan-serotype DENV inhibitor (EC50’s ranging from 0.057 to 11 nM against the four DENV serotypes). 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| fulltext | fulltext |
| identifier | ISSN: 0022-2623 |
| ispartof | Journal of medicinal chemistry, 2024-03, Vol.67 (5), p.4063-4082 |
| issn | 0022-2623 1520-4804 |
| language | eng |
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| source | MEDLINE; ACS Publications |
| subjects | Animals Dengue - drug therapy Dengue Virus Humans Hydrocarbons, Halogenated Indoles Mice Serogroup |
| title | Discovery of JNJ-1802, a First-in-Class Pan-Serotype Dengue Virus NS4B Inhibitor |
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