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Host targeted inhibitors of dengue virus and other viruses

a technology of dengue virus and inhibitors, applied in the field of host targeted inhibitors of dengue virus and other viruses, can solve the problems of no specific therapeutics, and achieve the effect of broader inhibitory activity and higher resistance barriers

Inactive Publication Date: 2018-09-20
PRESIDENT & FELLOWS OF HARVARD COLLEGE +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The patent refers to compounds that can be converted in the body into active drugs. These prodrugs have cleavable groups that can be solvolzed or under physiological conditions become the active drugs. Examples include choline ester derivatives and N-alkylmorpholine esters. These prodrug forms offer advantages of solubility, tissue compatibility, or delayed release in the body. The patent also mentions that acid derivatives, such as esters, amides, and anhydrides, can be used as prodrugs. The compounds described can be used to treat infectious diseases and delay or minimize symptoms associated with them. The therapeutically effective amount of a compound is the amount necessary to provide a therapeutic benefit in treating a condition. This can include improving overall therapy, reducing symptoms, or enhancing the effectiveness of other therapeutic agents.

Problems solved by technology

Despite the spread of the four DENV serotypes worldwide and the increasing incidence of DHF and DSS over the past fifty years, there currently are no specific therapeutics to combat DENV infection or a vaccine that protects against all four DENV serotypes.

Method used

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  • Host targeted inhibitors of dengue virus and other viruses
  • Host targeted inhibitors of dengue virus and other viruses
  • Host targeted inhibitors of dengue virus and other viruses

Examples

Experimental program
Comparison scheme
Effect test

example 1

of the Compounds

[0441]The compounds provided herein can be prepared from readily available starting materials using the following general methods and procedures. Various intermediates useful for preparation of the compounds of the invention can be prepared in accordance with methods described in the art (Upasani et al., J. Med. Chem. (1997) 40:73-84; and Hogenkamp et al., J. Med. Chem. (1997) 40:61-72) and using the appropriate reagents, starting materials, and purification methods known to those skilled in the art. Representative methods are demonstrated in Schemes 1-4. The compounds of the invention can be prepared using the intermediates described above. For example, a general method for preparing QL-XII-47 is illustrated in Scheme 1.

[0442]Compounds 1 (480 mg, 2 mmol, 1 equiv.) and 2 (470 mg, 2 mmol, 1 equiv.) were combined in 1,4-dioxane (13 mL) and heated at 100° C. for 4 h, cooled to room temperature, poured into brine, and extracted with ethyl acetate (3×). The organic phase ...

example 2

stal Structure of QL-X-138

[0458]QL-X-138 (see FIG. 7 for the chemical structure), a structural analog of QL-XII-47, has been successfully crystallized with EGFR kinase that contains a cysteine in the same position as the Tec-family kinases (FIG. 7). The structure shows the expected hydrogen bond between the quinoline nitrogen and the “hinge” region amino acid Met793. The pyrazole group is directed towards a hydrophobic pocket at the back of the ATP-pocket which the para-methyl aniline group is nestled beneath the P loop and a covalent bond with Cys797 is apparent.

example 3

d Mini-Screen of Acrylamide-Containing Compounds for the Identification of Novel Covalent Inhibitors of DENV

Methods

[0459]Small molecule screens (Chu et al., Proc. Nat. Acad. Sci. USA (2007) 104:3520-3525) and RNAi (Sessions et al., Nature (2009) 458:1047-1050) have been utilized to identify host factors that are required for Dengue virus (DENV) replication, with a particular interest in host kinases that modulate DENV replication. As an extension of this work, a cell-based mini-screen of a 30-compound subset of acrylamide-containing compounds was performed to identify novel covalent inhibitors of DENV. The compounds were designed to react covalently upon binding in the proper orientation near a reactive cysteine.

[0460]Huh7 cells were seeded in 24-well plates and infected at an MOI (multiplicity of infection) of 1 with 100 μl of DENV2 New Guinea C (DENV2-NGC). Plates were incubated for 1 hour at 37° C. and rocked every 15 min. Unadsorbed virus was removed by a PBS wash, after which 5...

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Abstract

Novel antiviral compounds of Formulae (I)-(III) are provided:The inventive compounds, pharmaceutical compositions thereof, and kits including the inventive compounds are useful for the prevention and treatment of infectious diseases caused by viruses, for example, by Flaviviridae virus (e.g., Dengue virus (DENV)), Kunjin virus, Japanese encephalitis virus, vesicular stomatitis virus (VSV), herpes simplex virus 1 (HSV-1), human cytomegalovirus (HCMV), poliovirus, Junin virus, Ebola virus, Marburg virus (MARV), Lassa fever virus (LASV), Venezuelan equine encephalitis virus (VEEV), or Rift Valley Fever virus (RVFV).

Description

RELATED APPLICATIONS[0001]The present invention is a continuation of and claims priority under 35 U.S.C. § 120 to U.S. application, U.S. Ser. No. 14 / 391,638, filed Oct. 9, 2014, which is a national stage filing under 35 U.S.C. § 371 of international PCT application, PCT / US2013 / 032488, filed Mar. 15, 2013, which claims priority under 35 U.S.C. § 119(e) to U.S. provisional application, U.S. Ser. No. 61 / 622,828, filed Apr. 11, 2012, each of which is incorporated herein by reference.GOVERNMENT SUPPORT[0002]This invention was made with government support under grant numbers HG006097, R01 AI076442, U54 CA156732-01, and U54 AI057159 awarded by the National Institutes of Health. The government has certain rights in the invention.BACKGROUND OF THE INVENTION[0003]Dengue virus (DENV) is one of the most significant mosquito-borne viral infections affecting humans today and is an NIAID (National Institute of Allergy and Infectious Diseases) Category A Biodefense pathogen. DENV is a plus-stranded...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): C07D471/04C07D519/00
CPCC07D519/00C07D471/04
Inventor GRAY, NATHANAEL S.YANG, PRISCILLA L.LIU, QINGSONGDE WISPELAERE, MÉLISSANNE
Owner PRESIDENT & FELLOWS OF HARVARD COLLEGE
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