Discovery of Acyl-Indole Derivatives as Pan-Serotype Dengue Virus NS4B Inhibitors

Abstract

In the absence of any approved dengue-specific treatment, the discovery and development of a novel small-molecule antiviral for the prevention or treatment of dengue are critical. We previously reported the identification of a novel series of 3-acyl-indole derivatives as potent and pan-serotype dengue virus inhibitors. We herein describe our optimization efforts toward preclinical candidates 24a and 28a with improved pan-serotype coverage (EC 50 's against the four DENV serotypes ranging from 0.0011 to 0.24 μM for 24a and from 0.00060 to 0.084 μM for 28a), chiral stability, and oral bioavailability in preclinical species, as well as showing a doseproportional increase in efficacy against DENV-2 infection in vivo in mice.

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

“…As reported previously, the introduction of either a 6-fluoro or 5-methyl-6-methoxy substitution pattern at the indole moiety provided the best overall combination of compound properties in the glycol series (exemplified by compounds 3a and 4a in Figure ). Transferring these indole substitution patterns to the sulfone series, either in combination with the para -fluorine substituent (compounds 10a and 12a ) or with the para -chlorine substituent (compounds 11a and 13a ), resulted in a further increase in the in vitro antiviral potency against all four DENV serotypes when compared to compound 8a , with activity against DENV-2 reaching subnanomolar EC 50 values for compounds 11a , 12a and 13a (Table ). The para -chlorine compounds 11a and 13a were more potent in vitro against all DENV serotypes compared to the para -fluorine compounds 10a and 12a , respectively.…”

“…To date, however, there is no structural information available on these membrane-bound target proteins and a lack of understanding of how the 3-acyl-indole inhibitors interact with the target. Further optimization of the different parts of the molecule (referred to as indole, top phenyl and aniline, as indicated in Figure ) was performed building on our previous learnings , and was guided by in vitro antiviral testing in Vero cells against four DENV strains, each representing one of the four DENV serotypes. In addition, in vitro antiviral activities and cytotoxicity in Vero cells infected with DENV-2/eGFP reporter virus were determined and are provided in the Supporting Information.…”

“…Additional modifications to the glycol-substituted compound 2a , primarily by the addition of substituents on the indole moiety and the top phenyl group, were subsequently explored when seeking to increase potency against all DENV serotypes (pan-serotype coverage) (Figure ). Introduction of halogens ( para -fluorine, para -chlorine) on the top phenyl moiety provided increased potency against all DENV serotypes and simultaneously blocked metabolization . Moreover, the addition of a methoxy-substituent at the ortho -position of the top phenyl group increased the chiral stability …”

“…We previously described the identification and structure–activity relationship (SAR) of a series of 3-acyl-indole derivatives that act as potent and pan-serotype inhibitors of DENV. , These inhibitors have been shown to block viral replication by preventing the interaction between the DENV nonstructural proteins NS3 and NS4B . To date, however, there is no structural information available on these membrane-bound target proteins and a lack of understanding of how the 3-acyl-indole inhibitors interact with the target.…”

“… Introduction of halogens ( para -fluorine, para -chlorine) on the top phenyl moiety provided increased potency against all DENV serotypes and simultaneously blocked metabolization . Moreover, the addition of a methoxy-substituent at the ortho -position of the top phenyl group increased the chiral stability …”