Discovery of JNJ-1802, a First-in-Class Pan-Serotype Dengue Virus NS4B Inhibitor.

Autor:	Kesteleyn B; Janssen Research & Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse 2340, Belgium., Bonfanti JF; Janssen Infectious Diseases Discovery, Janssen-Cilag, Chaussée du Vexin, Val de Reuil 27106, France., Bardiot D; CISTIM Leuven vzw, Bioincubator 2, Gaston Geenslaan 2, Leuven 3001, Belgium., De Boeck B; Janssen Research & Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse 2340, Belgium., Goethals O; Janssen Global Public Health R&D, Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse 2340, Belgium., Kaptein SJF; KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, Leuven 3000, Belgium., Stoops B; Janssen Research & Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse 2340, Belgium., Coesemans E; Janssen Research & Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse 2340, Belgium., Fortin J; Janssen Infectious Diseases Discovery, Janssen-Cilag, Chaussée du Vexin, Val de Reuil 27106, France., Muller P; Janssen Infectious Diseases Discovery, Janssen-Cilag, Chaussée du Vexin, Val de Reuil 27106, France., Doublet F; Janssen Infectious Diseases Discovery, Janssen-Cilag, Chaussée du Vexin, Val de Reuil 27106, France., Carlens G; CISTIM Leuven vzw, Bioincubator 2, Gaston Geenslaan 2, Leuven 3001, Belgium., Koukni M; CISTIM Leuven vzw, Bioincubator 2, Gaston Geenslaan 2, Leuven 3001, Belgium., Smets W; CISTIM Leuven vzw, Bioincubator 2, Gaston Geenslaan 2, Leuven 3001, Belgium., Raboisson P; Janssen Research & Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse 2340, Belgium., Chaltin P; CISTIM Leuven vzw, Bioincubator 2, Gaston Geenslaan 2, Leuven 3001, Belgium.; Centre for Drug Design and Discovery (CD3), KU Leuven, Bioincubator 2, Gaston Geenslaan 2, Leuven 3000, Belgium., Simmen K; Janssen Research & Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse 2340, Belgium., Loock MV; Janssen Global Public Health R&D, Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse 2340, Belgium., Neyts J; KU Leuven, Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, Laboratory of Virology and Chemotherapy, Herestraat 49, Leuven 3000, Belgium.; Global Virus Network (GVN), Baltimore, Maryland 21201, United States., Marchand A; CISTIM Leuven vzw, Bioincubator 2, Gaston Geenslaan 2, Leuven 3001, Belgium., Jonckers THM; Janssen Research & Development, Janssen Pharmaceutica NV, Turnhoutseweg 30, Beerse 2340, Belgium.
Jazyk:	angličtina
Zdroj:	Journal of medicinal chemistry [J Med Chem] 2024 Mar 14; Vol. 67 (5), pp. 4063-4082. Date of Electronic Publication: 2024 Feb 28.
DOI:	10.1021/acs.jmedchem.3c02336
Abstrakt:	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 (EC 50 '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.
Databáze:	MEDLINE
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