GS-5806 is a novel, orally bioavailable RSV fusion inhibitor discovered following a lead optimization campaign on a screening hit. The oral absorption properties were optimized by converting to the pyrazolo[1,5-a]-pyrimidine heterocycle, while potency, metabolic, and physicochemical properties were optimized by introducing the para-chloro and aminopyrrolidine groups. A mean EC50 = 0.43 nM was found toward a panel of 75 RSV A and B clinical isolates and dose-dependent antiviral efficacy in the cotton rat model of RSV infection. Oral bioavailability in preclinical species ranged from 46 to 100%, with evidence of efficient penetration into lung tissue. In healthy human volunteers experimentally infected with RSV, a potent antiviral effect was observed with a mean 4.2 log10 reduction in peak viral load and a significant reduction in disease severity compared to placebo. In conclusion, a potent, once daily, oral RSV fusion inhibitor with the potential to treat RSV infection in infants and adults is reported.

Cyclophilins are a family of peptidyl-prolyl isomerases that are implicated in a wide range of diseases including hepatitis C. Our aim was to discover through total synthesis an orally bioavailable, non-immunosuppressive cyclophilin (Cyp) inhibitor with potent anti-hepatitis C virus (HCV) activity that could serve as part of an all oral antiviral combination therapy. An initial lead 2 derived from the sanglifehrin A macrocycle was optimized using structure based design to produce a potent and orally bioavailable inhibitor 3. The macrocycle ring size was reduced by one atom, and an internal hydrogen bond drove improved permeability and drug-like properties. 3 demonstrates potent Cyp inhibition ( K = 5 nM), potent anti-HCV 2a activity (EC = 98 nM), and high oral bioavailability in rat (100%) and dog (55%). The synthetic accessibility and properties of 3 support its potential as an anti-HCV agent and for interrogating the role of Cyp inhibition in a variety of diseases.

Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infections in infants and young children. In addition, RSV causes significant morbidity and mortality in hospitalized elderly and immunocompromised patients. Currently, only palivizumab, a monoclonal antibody against the RSV fusion (F) protein, and inhaled ribavirin are approved for the prophylactic and therapeutic treatment of RSV, respectively. Therefore, there is a clinical need for safe and effective therapeutic agents for RSV infections. H uman respiratory syncytial virus (RSV) is the predominant cause of bronchiolitis and pneumonia in infants and young children (1). Those most at risk for severe RSV disease are infants born prematurely (Ͻ34 weeks gestation) or less than 6 weeks of age and children with underlying medical conditions, such as bronchopulmonary dysplasia, congenital heart disease, or immunodeficiency (1-3). Severe RSV infection in children less than 1 year old is associated with recurrent wheezing and asthma later in life (4). RSV is also an important cause of lower respiratory tract infections in immunocompromised individuals and the elderly, often resulting in significant morbidity and mortality (5-7).Currently, there is no effective vaccine available for the prevention of RSV infection. Current approved therapeutic options for RSV include palivizumab (Synagis), a neutralizing monoclonal antibody against the RSV F protein, and inhaled ribavirin (Virazole), a broad-spectrum nucleoside analog targeting RNA transcription/replication. Palivizumab is approved for the prophylactic treatment of pediatric patients at high risk of developing severe RSV infection, whereas ribavirin is the only antiviral approved for RSV treatment (8). However, contradictory observations regarding the efficacy, concerns about tolerability, and challenging routes of administration have significantly limited the use of inhaled ribavirin (9). Therefore, there is a clinical need for a safe and effective therapeutic for pediatric and adult RSV infections. Recently, a number of small-molecule RSV inhibitors have been identified. These inhibitors partition into three categories based upon their different mechanisms of action: (i) nucleocapsid protein inhibitors (RSV604) (10), (ii) RNA-dependent RNA polymerase inhibitors (YM-53403, BI-D, and ALS-8176) (11-13), and (iii) fusion inhibitors (VP-14637, TMC-353121, BMS-433771, and GS-5806) (14-17). Among these, RSV fusion inhibitors are the most potent class in vitro and exhibit efficacy in animal models of RSV infection (14-17). Currently, only ALS-8176 and GS-5806 are being clinically developed for the treatment of RSV infection.RSV is an enveloped virus with a negative-sense, single-stranded RNA genome. RSV infection is initiated by attachment of the viral glycoprotein (G) to the cell surface. Following attachment, the RSV fusion protein (F) mediates fusion of the viral and cellular membranes, allowing the viral replication complex to enter the cell. Spread of RSV infection occurs either through cel...

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Hepatitis C virus (HCV) is a major global public health problem. While the current standard of care, a direct-acting antiviral (DAA) protease inhibitor taken in combination with pegylated interferon and ribavirin, represents a major advancement in recent years, an unmet medical need still exists for treatment modalities that improve upon both efficacy and tolerability. Towards those ends, much effort has continued to focus on the discovery of new DAAs, with the ultimate goal to provide interferon-free combinations. The RNA-dependent RNA polymerase enzyme NS5B represents one such DAA therapeutic target for inhibition which has attracted much interest over the past decade. Herein, we report the discovery and optimization of a novel series of inhibitors of HCV NS5B, through the use of structure-based design applied to a fragment-derived starting point. Issues of potency, pharmacokinetics and early safety were addressed in order to provide a clinical candidate in fluoropyridone 19.