Viral Replication Inhibitors May Treat the Dengue Virus Infections

Patent Application Title:	Mono- or Disubstituted Indole Derivatives as Dengue Viral Replication Inhibitors
Patent Application Number:	WO 2016/180696 A1	Publication date:	17 November 2016
Priority Application:	EP 15166900.9	Priority date:	8 May 2015
	EP 16163342.5		31 March 2016
Inventors:	Kesteleyn, B. R. R.; Bonfanti, J.-F.; Jonckers, T. H. M.; Raboisson, P. J.-M. B.; Bardiot, D. A. M.-E.; Marchand, A. D. M.
Applicant:	Janssen Pharmaceuticals, Inc.; 1125 Trenton-Harbourton Road, Titusville, New Jersey 08560, USA
	Katholieke Universiteit Leuven; KU Leuven Research & Development, Waaistraat 6, bus 5105, 3000 Leuven (BE)
Disease Area:	Dengue viral infections	Biological Target:	Replication of the Dengue virus

Summary:	The invention in this patent application relates to indole derivatives represented generally by formula (I) that inhibit the replication of the Dengue virus and can potentially be used for the treatment and/or prevention of the Dengue viral infections.
	The Dengue virus (DENV) is a mosquito-borne single positive-stranded RNA virus that belongs to the genus Flavivirus of the Flaviviridae family. There are four known distinct, but closely related serotypes of the Dengue virus named DENV-1, 2, 3, and 4. Infections with this virus causes an endemic disease in tropical and subtropical regions known as the Dengue fever (DF). The disease is associated with high fever, headache, vomiting, muscle and joint pain, as well as skin rash. In a few cases, the disease may become a life-threatening condition known as Dengue hemorrhagic fever (DHF), which causes bleeding, low blood platelet counts, and blood plasma leakage. It may develop further into Dengue shock syndrome (DSS) that causes dangerously low blood pressure. The year 2000 World Health Organization (WHO) report estimated that 2.5 billion people including 1 billion children are at risk of DENV infection, which causes more than 20,000 deaths worldwide each year.
	The past few years have witnessed significant increase in Dengue infection outbreaks and spreading of the virus into new regions in many Latin America, South-East Asia, and the Western Pacific countries. In addition, the outbreaks tend to be more severe.
	The prevention and/or control of the Dengue viral infection rely mostly on eradication of mosquitoes and vaccination.
	Mosquitoes such as Aedes aegypti and Aedes albopictus (tiger mosquito) that carry the Dengue virus are moving north on the globe and spreading the disease into newer locations such as southern Texas and parts of Europe.
	Researchers have made noticeable improvements in the development of Dengue vaccines; however, application of vaccines is associated with many difficulties including the existence of antibody-dependent enhancement (ADE), which happens as a result of multiple infections with different serotypes. Infection by one serotype provides the recovered patient with a lifelong immunity against that specific serotype but can only provide partial and transient protection against the other serotypes. Studies have shown that if a recovered patient is infected with another serotype, the preexisting heterologous antibodies from the previous infection can complex with the newly infecting Dengue virus serotype but that does not neutralize the pathogen. Instead it seems to facilitate the virus entry into the cells, which can cause an uncontrolled virus replication, higher peak viral titers, and more severe Dengue disease. Since maternal antibodies can easily transfer from mothers to infants by breast feeding, this might explain the reason why children are more vulnerable to severe Dengue infections than adults.
	The term Dengue hyperendemic regions refers to locations with two or more simultaneously circulating Dengue serotypes. People living in these regions are exposed to a significantly higher risk of secondary, more severe infections. Additionally, there is an increased probability for the emergence of more virulent Dengue strains, which in turn augment the probability of DHF and DSS.
	Recently, Sanofi Pasteur had successfully produced a Dengue vaccine that was approved for use in Mexico, Brazil, the Philippines, and El Salvador. The vaccine is still under regulatory review and expected to be approved in many other countries that contain endemic regions. While the vaccine is a game changer and offers protection to a large part of the population, it has limited efficacy, especially against DENV-1 and DENV-2, shows low efficacy in flavivirus-naïve subjects, and requires lengthy dosing schedule (3 doses on a 0/6/12-month schedule). The vaccine is not likely to be effective with very young infants, who bear the largest burden of Dengue infections.
	Currently, there are no available antiviral drugs specific for the treatment or prevention of Dengue fever virus infection. Thus, there is a great unmet medical need for effective therapeutics for the prevention or treatment of viral infections caused by Flaviviruses, particularly the Dengue virus. The desirable therapeutics should possess good antiviral potency, have no or low levels of side-effects, show a broad spectrum activity against multiple Dengue virus serotypes, low toxicity, and/or good pharmacokinetic properties.
	The compounds described in this patent application are inhibitors of the Dengue virus replication. They show high potency against all four known serotypes of the Dengue virus and possess good pharmacokinetic profiles. They may thus provide useful treatment and/or prevention of the infections with Dengue viruses.
Important Compound Classes:
Key Structures:	The inventors described the structures and synthesis of 11 racemic compounds of formula (I). Each racemic compound was resolved into its two enantiomers (A and B) using chiral supercritical fluid chromatography (SFC); the absolute stereochemistry of enantiomers was not specified. The following are representative examples; the stereogenic centers are marked with *:
Biological Assay:	DENV-2 antiviral assay Tetravalent reverse transcriptase quantitative-PCR (RT-qPCR) assay. Protocol A: compounds were tested against DENV-1 strain TC974#666, DENV-2 strain 16681, DENV-3 strain H87, and DENV-4 strains H241 and SG/06K2270DK1/2005 Tetravalent quantitative reverse transcriptase-PCR (RT-qPCR) assay. Protocol B: compounds were tested against DENV-1 strain Djibouti (D1/H/IMTSSN98/606), DENV-2 strain NGC, DENV-3 strain H87, and DENV-4 strain SG/06K2270DK1/2005 Cytotoxic assay
Biological Data:	Biological data obtained from testing the above representative examples in the DENV-2 antiviral assay are listed in the following table:
Recent Review Articles:	1. Rondina M. T.; Weyrich A. S.. Blood 2015, 126 ( (3), ), 286–287.
	2. Lim S. P.; Wang Q.-Y.; Noble C. G.; Chen Y.-L.; Dong H.; Zou B.; Yokokawa F.; Nilar S.; Smith P.; Beer D.; et al. Antiviral Res. 2013, 100 ( (2), ), 500–519.
	3. Woodland D. L.Viral Immunol. 2015, 28 ( (2), ), 75–75.

The author declares no competing financial interest.