Human rhinoviruses (HRVs) are non-enveloped, positive-sense single-stranded RNA viruses which are the most common cause of upper respiratory illness including the common cold. While most HRV infections are mild and self-limiting, in susceptible populations they can lead to exacerbations in asthma and COPD which often require hospitalization. Currently there are no marketed antivirals against HRV although capsid-binding compounds pleconaril, pirodavir and vapendavir, which target the HRV structural protein VP1 have been in clinical development. Pleconaril, the most advanced HRV inhibitor, produced significant reductions in the severity and duration of exacerbations in clinical trials; however, it has unfavorable physicochemical properties and drug interaction concerns. We initiated a project to identify a novel broad-spectrum capsid-binding antirhinoviral with improved physicochemical properties, pharmacokinetics (PK) and CYP induction profile compared to pleconaril and other VP1 inhibitors reported in the literature.<br/>The VP1 antiviral binding site is a largely hydrophobic tunnel and while the logD reported for most published inhibitors is &gt;4 we determined that broad serotype coverage was best accomplished by generating compounds within a relatively narrow logD<sub>(pH=7.4)</sub> range of 2.0 – 2.4. In general, these compounds also possessed improved solubility and higher free fraction. Additional exploration of functional group tolerance, the effect of sterics and incorporating chirality resulted in analogues having improved in vitro PK, metabolic stability and CYP induction profiles. Ultimately we identified a compound, AZN001, that had favorable physicochemical properties and an improved in vitro safety profile while demonstrating excellent potency against an expanded 46-serotype HRV panel. Consequently, AZN001 was progressed into preclinical in vivo safety and tolerability studies.

Discovery of AZN001: A broad-spectrum capsid-binding human rhinovirus inhibitor

252nd National Meeting (2016)

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