1,4-Benzodiazepines as Inhibitors of Respiratory Syncytial Virus. The Identification of a Clinical Candidate

Henderson, Elisa A.; Alber, Dagmar; Baxter, Robert C.; Bithell, Sian K.; Budworth, Joanna; Carter, Malcolm C.; Chubb, Ann; Cockerill, G. Stuart; Dowdell, Verity C. L.; Fraser, I. J.; Harris, R. Adron; Keegan, Sally J.; Kelsey, Richard D.; Lumley, James; Stables, Jeremy N.; Weerasekera, Natasha; Wilson, Lara J.; Powell, Kenneth L.

doi:10.1021/jm060747l

Cited by 48 publications

(47 citation statements)

References 25 publications

(82 reference statements)

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“…An early derivative, A-57400, showed improved activity but also showed some growth inhibitory effects at 50 M. Separation of the two isomers of A-33903 demonstrated that the antiviral activity was associated with the S enantiomer (15). Therefore, all subsequent compounds of this series tested were the isolated S enantiomers.…”

Section: Profile Of Rsv604mentioning

confidence: 96%

RSV604, a Novel Inhibitor of Respiratory Syncytial Virus Replication

Chapman¹,

Abbott²,

Alber³

et al. 2007

Antimicrob Agents Chemother

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123

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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.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, resulting in up to 125,000 hospitalizations annually in the United States (3). The infants most at risk of severe disease are those under 6 weeks of age, those with bronchopulmonary dysplasia, congenital heart disease, or immunodeficiency, and those born prematurely. Hospital admission rates for these groups range between 5% and 30% (20,25). The mortality rate among children admitted to hospital is approximately 3% for those with heart and lung problems and up to 1% for those without these risk factors (11,25). In adults and the elderly, RSV pneumonia is increasingly recognized as a significant cause of morbidity and mortality, being associated with more than 17,000 deaths annually between 1991 and 1998 (9, 22). Among the hospitalized elderly, mortality can be as high as 10 to 20%, and among severely immunocompromised patients with RSV pneumonia, it can be on the order of 50 to 70% (10). There is therefore an urgent and unmet medical need for novel therapies to deal with infections caused by this virus.The development of new therapeutics for RSV was recently reviewed (17,19). Although research into the prevention and treatment of RSV infection has been ongoing for almost 40 years, vaccine development is difficult (8, 13), and to date, there is no clinically approved vaccine. 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 (21). These include infants born prematurely and those with congenital conditions. Because the antibody has to be given prophylactically and treatment is very expensive, its use is limited mainly to developed countries. The effect...

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Section: Profile Of Rsv604mentioning

confidence: 96%

RSV604, a Novel Inhibitor of Respiratory Syncytial Virus Replication

Chapman¹,

Abbott²,

Alber³

et al. 2007

Antimicrob Agents Chemother

Self Cite

123

View full text Add to dashboard Cite

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“…The synthesis of new 1H-imidazole-4,5-dimethyl dicarboxylate (1-4), 1H-imidazole-4,5-diamide (5)(6)(7)(8), imidazole [4,5-e] [1,3]diazepine-4,8-dione (9-11) and acyclic carbamoyl imino-ureido imidazole derivatives (12 and 13) is performed according to the Figure 2. [4,5-e] [1,3]diazepine-4,8-dione (9-11) and ureido-imino-carbamoyl-imidazole derivatives (12-13).…”

Section: Chemistrymentioning

confidence: 99%

“…There is a clear need for new anti-RSV therapeutics, with improved efficacy and safety for broader applications [3]. Powell and his colleagues have recently identified a new class of RSV inhibitors, namely 1,4-benzodiazepines [4], which eventually led to identification of RSV604 as a clinical candidate [5].…”

Section: Introductionmentioning

confidence: 99%

“…In the light of these findings we efficiently synthesized a series of new 1H-imidazole-4,5-dicarboxylic acid/amide derivatives (1)(2)(3)(4)(5)(6)(7)(8), imidazo [4,5-e] [1,3]diazepine-4,8-dione derivatives (9-11) and carbamoyl imino-ureido derivatives of imidazole (12 and 13) ( Figure 1) and evaluated their antiviral and cytostatic activity potency.…”

Section: Introductionmentioning

confidence: 99%

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The Novel [4,5-e][1,3]Diazepine-4,8-dione and Acyclic Carbamoyl Imino-Ureido Derivatives of Imidazole: Synthesis, Anti-Viral and Anti-Tumor Activity Evaluations

et al. 2013

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Abstract:In the present paper, we report on the synthesis, and in vitro antiviral and cytostatic activities of a series of novel imidazole [4,5-e][1,3]diazepine-4,8-dione (compounds 9-11) and acyclic carbamoyl imino-ureido imidazole (compounds 12 and 13) derivatives. These new type of chemical entities showed no significant activity on the broad spectrum of DNA and RNA viruses. Results of antiproliferative assays performed on a panel of selected human tumor cell lines revealed that only compounds 1 and 5 showed moderate and selective cytostatic effect against HeLa cells (IC 50 = 24 and 32 µM) with no concomitant cytotoxic effects on human normal fibroblasts (BJ). Importantly, an imidazole derivative containing a pyrrolidine moiety linked via an ethylenic spacer (3) showed a selective cytostatic effect toward cervical carcinoma (HeLa) cells (IC 50 = 9.5 µM) with OPEN ACCESSMolecules 2013, 18 13386 no apparent cytotoxicity on human normal fibroblasts (BJ). This compound can be therefore considered as a potential anti-tumor lead compound for further synthetic structure optimization.

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“…Virazole has shown equivocal efficacy in bone marrow transplant patients and is not typically used to treat infants with RSV due to poor efficacy and tolerability, as well as the complexity of the specialized aerosol drug delivery system (14)(15)(16). A number of small-molecule inhibitors of RSV have been evaluated as potential therapeutics for treating RSV infections that target viral entry and replication (17)(18)(19)(20)(21)(22)(23). While several clinical candidates have been evaluated in human studies, only ribavirin has been approved for the treatment of RSV infection.…”

mentioning

confidence: 99%