RV521 is an orally bioavailable inhibitor of respiratory syncytial virus (RSV) fusion that was identified after a lead optimization process based upon hits that originated from a physical property directed hit profiling exercise at Reviral. This exercise encompassed collaborations with a number of contract organizations with collaborative medicinal chemistry and virology during the optimization phase in addition to those utilized as the compound proceeded through preclinical and clinical evaluation. RV521 exhibited a mean IC50 of 1.2 nM against a panel of RSV A and B laboratory strains and clinical isolates with antiviral efficacy in the Balb/C mouse model of RSV infection. Oral bioavailability in preclinical species ranged from 42 to >100% with evidence of highly efficient penetration into lung tissue. In healthy adult human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a significant reduction in viral load and symptoms compared to placebo.

Effective treatments for respiratory syncytial virus (RSV) infection are lacking. Here, we report a human proof-of-concept study for RV521, a small-molecule antiviral inhibitor of the RSV-F protein. In this randomized, double-blind, placebo-controlled trial, healthy adults were challenged with RSV-A Memphis-37b. ABSTRACT Effective treatments for respiratory syncytial virus (RSV) infection are lacking. Here, we report a human proof-of-concept study for RV521, a small-molecule antiviral inhibitor of the RSV-F protein. In this randomized, double-blind, placebo-controlled trial, healthy adults were challenged with RSV-A Memphis-37b. After infection was confirmed (or 5 days after challenge virus inoculation), subjects received RV521 (350 mg or 200 mg) or placebo orally every 12 h for 5 days. The primary endpoint was area under the curve (AUC) for viral load, as assessed by reverse transcriptase quantitative PCR (RT-qPCR) of nasal wash samples. The primary efficacy analysis set included subjects successfully infected with RSV who received ≥1 dose of study drug. A total of 66 subjects were enrolled (n = 22 per group); 53 were included in the primary analysis set (RV521 350 mg: n = 16; 200 mg: n = 18; placebo: n = 19). The mean AUC of RT-qPCR-assessed RSV viral load (log10 PFU equivalents [PFUe]/ml · h) was significantly lower with RV521 350 mg (185.26; standard error [SE], 31.17; P = 0.002) and 200 mg (224.35; SE, 37.60; P = 0.007) versus placebo (501.39; SE, 86.57). Disease severity improved with RV521 350 mg and 200 mg versus placebo (P = 0.002 and P = 0.009, respectively, for AUC total symptom score [score × hours]). Daily nasal mucus weight was significantly reduced (P = 0.010 and P = 0.038 for RV521 350 mg and 200 mg, respectively, versus placebo). All treatment-emergent adverse events were grade 1 or 2. No subjects discontinued due to adverse events. There was no evidence of clinically significant viral resistance, and only three variants were detected. RV521 effectively reduced RSV viral load and disease severity in humans and was well tolerated. (This study has been registered at ClinicalTrials.gov under registration no. NCT03258502.)

Inhibitors of the respiratory syncytial virus (RSV) fusion protein block entry of the virus into the cell and have shown varying efficacy in a human challenge model of RSV disease. Trials in patient populations are yet to show significant benefits. Jonckers et al. ( J. Med. Chem. 2020, DOI: 10.1021/acs.jmedchem.0c00226) describe the discovery of JNJ-53718678 which can now claim the leading position in clinical evaluation. For RSV inhibitors, the current status of the clinical development of the compound is discussed.

Dengue is considered a critical worldwide health concern with an estimated 3.6 billion people at risk of infection and approximately 390 million infected annually of which 96 million are present with clinically overt disease. Most subjects recover from Dengue incurring asymptomatic or subclinical disease; however, progression can take the form of more dangerous dengue fever (DF), most severe dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS). Dengue virus (DENV) belongs to the Flaviviridae family of single positive-stranded ribonucleic acid viruses of the genus Flavivirus. Although a DENV vaccine with variable serotype efficacy is available, there is still an urgent need to develop small molecule inhibitors to support the treatment of DHF and DSS. The chapter presents a summary of drugs repurposed as DENV inhibitors and even though most did not demonstrate substantial efficacy they represent a suitable and advanced starting point to develop new treatments.

Respiratory syncytial virus (RSV) is a globally prevalent viral infection with limited treatment options which hospitalizes millions each year. Treatment options have been limited to palivizumab, a monoclonal antibody, approved for prophylaxis in high-risk infants and ribavirin with very limited efficacy and significant safety concerns. This Perspective surveys the range of direct acting antiviral agents (DAAs) that target key steps in the viral life cycle. A number of approaches to DAAs have produced landmark clinical studies over the past few years, notably in fusion and nucleoside inhibitors, and an update of the clinical status of these compounds is provided. Non-nucleoside inhibitors of replication are reviewed in addition to inhibitors of other mechanisms, notably the RSV N and G proteins. This article will provide an informative perspective of the current status of drug discovery targeted at providing an effective therapy for RSV infection.

After the great success of the research and development of antiviral drugs to treat chronic infections like HIV and hepatitis C, attention is turning to treatment of acute viral infections. In this article, we illustrate the potential for developing antiviral drugs to treat such infections. Four distinct clinical problems caused by four different viruses allow exploration of the problems associated with each disease. Targets for each virus are evaluated, and the progress made to date in identifying suitable clinical candidates is discussed. Finally, we consider the problem of emerging acute virus infections and improving rapidity of responses to them.

Tykerb (lapatinib) is a successful medicine for the treatment of a subset of solid tumours driven by aberrant signalling in tumour cells that could be selectively targeted over healthy, normal tissue. The lessons learnt from the discovery and development of lapatinib can serve as a key learning tool in pharmaceutical project management as much as a study in scientific insight. The research team operated without the benefit of protein crystal structure information whilst the knowledge of the ERBB family of biological targets and the required inhibition profile of an effective molecule grew as the project progressed. In brief, because it was a new area of oncology with huge potential for dramatically improved treatments, it was a question of knowing when to be flexible and when to be rigid; of knowing what to change and what to retain. Fundamentals like retaining a strong link between in vitro and in vivo assays were constant throughout the lifetime of the project; progression criteria could be more flexible. Outstanding synthetic design was core to the success of the project, allowing the rapid evaluation of diversely functionalized, high quality small molecules, thus creating a robust drug discovery knowledge base. In the earlier days of the project, the emphasis was on data acquisition and SAR, whereas the success of the selection of GW2016 for clinical study lay in the application of the acquired understanding for the candidate target profile developed throughout the project.

This chapter contains sections titled: Introduction Discovery Synthesis Preclinical Pharmacokinetic and Toxicology Phase I-III Safety and Efficacy Future Directions References

The biphenyl amides (BPAs) are a series of p38α MAP kinase inhibitors. Compounds are able to bind to the kinase in either the DFG-in or DFG-out conformation, depending on substituents. X-ray, binding, kinetic and cellular data are shown, providing the most detailed comparison to date between potent compounds from the same chemical series that bind to different p38α conformations. DFG-out-binding compounds could be made more potent than DFG-in-binding compounds by increasing their size. Unexpectedly, compounds that bound to the DGF-out conformation showed diminished selectivity. The kinetics of binding to the isolated enzyme and the effects of compounds on cells were largely unaffected by the kinase conformation bound.

Publisher Summary Human respiratory syncytial virus (RSV) is the most important respiratory pathogen that causes lower respiratory tract infections such as bronchiolitis and pneumonia in infants and young children. The disruption of viral attachment and entry to cells is a common strategy in the design of antiviral therapies, as evidenced by successful approaches to influenza and HIV inhibition. Several compound types have been described and two are reported as having progressed into early clinical development. Leading the field currently are a series of benzimidazole pyridines. Ribavirin was the first and remains the only small molecule inhibitor of RSV approved for clinical use. Recently the effect of PPARγ agonists in cell culture was investigated, specifically Rosiglitazone™ and Ciglitazone™. These compounds effectively protected A549, Hep-2 cells and normal human bronchial epithelial cells against RSV induced cytotoxicity and syncytia formation. K. Sudo and co-workers have described a series of benzazepine thiophenes with submicromolar activity in plaque-reduction assays against RSV. YM53403 displays an EC 50 of 200nM with a selectivity index of 412. The development of RSV vaccines for use in young infants has been complicated by reduced immune responses in this age group due to immunologic immaturity and the immunosuppressive effects of maternal antibodies. Passive immunization with the monoclonal antibody palivizumab (Synagis®) has provided about 50% protection to high-risk children.

The biphenyl amides are a novel series of p38 MAP kinase inhibitors. Structure-activity relationships of the series against p38alpha are discussed with reference to the X-ray crystal structure of an example. The series was optimised rapidly to a compound showing oral activity in an in vivo disease model.

ABSTRACT Respiratory syncytial virus (RSV) is the most common cause of lower respiratory tract infections worldwide, yet no effective vaccine or antiviral treatment is available. Here we report the discovery and initial development of RSV604, a novel benzodiazepine with submicromolar anti-RSV activity. It proved to be equipotent against all clinical isolates tested of both the A and B subtypes of the virus. The compound has a low rate of in vitro resistance development. Sequencing revealed that the resistant virus had mutations within the nucleocapsid protein. This is a novel mechanism of action for anti-RSV compounds. In a three-dimensional human airway epithelial cell model, RSV604 was able to pass from the basolateral side of the epithelium effectively to inhibit virus replication after mucosal inoculation. RSV604, which is currently in phase II clinical trials, represents the first in a new class of RSV inhibitors and may have significant potential for the effective treatment of RSV disease.

Respiratory syncytial virus (RSV) is the cause of one-fifth of all lower respiratory tract infections worldwide and is increasingly being recognized as representing a serious threat to patient groups with poorly functioning or immature immune systems. Racemic 1,4-benzodiazepines show potent anti-RSV activity in vitro. Anti-RSV evaluation of 3-position R- and S-benzodiazepine enantiomers and subsequent optimization of this series resulted in selection of a clinical candidate. Antiviral activity was found to reside mainly in the S-enantiomer, and the R-enantiomers were consistently less active against RSV. Analogues of 1,4-(S)-benzodiazepine were synthesized as part of the lead optimization program at Arrow and tested in the XTT assay. From this exercise, (S)-1-(2-fluorophenyl)-3-(2-oxo-5-phenyl-2,3-dihydro-1H-benzo[e][1,4]-diazepin-3-yl)-urea, 17b (RSV-604) was identified as a clinical candidate, exhibiting potent anti-RSV activity in the XTT assay, which was confirmed in secondary assays. Compound 17b also possessed a good pharmacokinetic profile and has now progressed into the clinic.

The biphenyl amides (BPAs) are a novel series of p38 MAP kinase inhibitors. The discovery of the series through structure-based focused screening is described, and the binding mode of the compounds is explained with reference to X-ray crystal structures.