Alphaviruses represent a new and emerging public health threat. These viruses share several characteristics: they infect humans, invade the central nervous system (CNS), are mosquito-borne, and are weaponizable. The focus of our research is the development of novel, indole-based compounds to intervene with infection. Initial HTS screening for inhibitors of alphavirus RNA replication identified the thienopyrrole CCG-32091 (IC50= 24 �M), which was successfully replaced with the indole analog CCG-102516 (IC50= 15 �M) to avoid predicted metabolic and chemical instability. SAR investigations sought to improve potency, minimize cytotoxicity and bring the physico-chemical properties of CCG-102516 within the range of successful CNS drugs by reducing molecular weight and polar surface area. In addition to antiviral activity, analogs were evaluated for P-glycoprotein (Pgp) interaction and passive membrane permeability in order to assess potential CNS permeability and predicted oral bioavailability. The compounds exhibited high permeability but demonstrated structure-dependent interaction with Pgp.

Development of novel small molecule inhibitors of alphavirus replication

243rd National Meeting (2012)

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