Delivery of pharmacologically active nucleoside triphosphate analogs to sites of viral infection is challenging. In prior work we identified a 2'-C-methyl-1'-cyano-7-deaza-adenosine C-nucleotide analog with desirable selectivity and potency for the treatment of HCV infection. However, the prodrug selected for clinical development, GS-6620, required a high dose for meaningful efficacy and had unacceptable variability due to poor oral absorption as a result of suboptimal solubility, intestinal metabolism and efflux transport. While obtaining clinical proof of concept for the nucleotide analog, a more effective prodrug strategy would be necessary for clinical utility. Here we report an alternate prodrug of the same nucleoside analog identified to address liabilities of GS-6620. A phosphoramidate prodrug containing the non-proteinogenic amino acid methylalanine, an isopropyl ester and phenol in the (S) conformation at phosphorous, GS2, was found to have improved solubility, intestinal stability and hepatic activation. GS2 is a more selective substrate for hepatically expressed carboxyl esterase (CES) 1 and is resistant to hydrolysis by more widely expressed hydrolases including cathepsin A (CatA) and CES2. Unlike GS-6620, GS2 was not cleaved by intestinally expressed CES2 and as a result, was stable in intestinal extracts. Levels of liver triphosphate following oral administration of GS2 in animals were higher than GS-6620 even when administered under optimal conditions for GS-6620 absorption. Combined these properties suggest that GS2 will have better oral absorption in the clinic when administered in a solid dosage form and the potential to extend the clinical proof of concept obtained with GS-6620.
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