Due to the limit in therapeutic options for human respiratory syncytial virus (RSV), a high throughput screen of the NIH Molecular Libraries Small Molecule Repository (MLSMR) was carried out with a focus on identifying novel, small molecule inhibitors that could be optimized through a medicinal chemistry effort utilizing structure-activity relationships.  Hit compounds were validated and optimized for potency and HEp-2 cellular cytotoxicity. Pursuit of a sulfonylpyrrolidine hit scaffold resulted in a compound that inhibited a virus-induced cytopathic effect in the entry stage of infection (EC50 = 2.25 � 0.82 �M).  The inhibitor demonstrated marginal cytotoxicity (CC50 = 30.91 � 1.09 �M) and reduced viral titer by 200-fold as determined by a plaque reduction assay.  Compared to Ribavirin, the only FDA-approved RSV small molecule available, the sulfonylpyrrolidine inhibitor obtained from this effort demonstrated an improved in vitro potency and therapeutic window.

Discovery and development of sulfonylpyrrolidine compounds that inhibit human respiratory synctial virus activity

243rd National Meeting (2012)

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