Baumert, Eric Robinet PURPOSE: To determine the intracellular metabolism of a novel anti-HCV β-D-2′-C-methyl-2,6-diaminopurine ribonucleoside (DAPN) phosphoramidate (RS-1389) in comparison to BMS-986094 (formerly know as INX-189), a related ribonucleoside analog which was halted in phase IIb due

to cardiac adverse effects. METHODS: RS-1389 was compared to BMS-986094 and IDX-184 side-by-side for interspecies plasma stability and intracellular metabolism in primary hepatocytes and human cardiomyocytes. RESULTS: In human plasma, all three compounds had half-lives longer than 24 hr. However, in mouse and rat plasma, RS-1389 Atezolizumab cost and BMS-986094 were rapidly metabolized (TV2 were less than 5 min). In dog and monkey plasma, the half-live of RS-1389 was shorter when compared with those of BMS-986094 and IDX-184. In Huh-7, HepG2 cells and all five species (mouse, rat, dog, monkey and human) of primary hepatocytes, RS-1389 was metabolized into two nucleoside triphosphates: 2′-C-methyl-DAPN-TP and 2′-C-meth- yl-GTP. BVD-523 solubility dmso In Huh-7 and HepG2 cells, BMS-986094 produced

the highest levels of 2′-C-methyl-GTP within 4 hr, more than 78-fold higher than the total nucleoside 5′-triphosphate inhibitors (NI-TP) from RS-1389 or IDX-184. However, in primary human hepatocytes, RS-1389 produced more NI-TP than BMS- 986094 and IDX-184, with the novel 2′-C-methyl-DAPN-TP as the predominant metabolite. Notably, in human cardiomyo-cytes, BMS-986094 generated extremely high levels (> 8-fold) of 2′-C-methyl-GTP, when compared to RS-1389 and IDX-184. CONCLUSIONS: RS-1389 demonstrated comparable stability in human plasma to BMS-986094 and IDX-184; delivered predominantly 2′-C-methyl-DAPN-TP ADP ribosylation factor and a relatively small amount of 2′-C-methyl-GTP in primary human hepatocytes. Importantly, less NI-TP levels were produced with RS-1389 in human cardio-myocytes, suggesting greater safety compared to BMS-986094 and IDX-184, and warranting

further investigation as an anti-HCV preclinical purine nucleoside candidate. Disclosures: Steven J. Coats – Employment: RFS Pharma Raymond F. Schinazi – Board Membership: RFS Pharma, LLC; Stock Shareholder: RFS Pharma, LLC The following people have nothing to disclose: Sijia Tao, Zhou Longhu, Hong-wang Zhang, Shaoman Zhou, Sheida Amiralaei, Jadd Shelton For decades, the chimpanzee model has been the only system for studying HCV infection and evaluation of antiviral compounds. However limited availability, significant costs, and ethical considerations make the chimpanzee model increasingly impractical today. A simple, reproducible noninfectious HCV mouse efficacy model would provide valuable information for compounds before entering clinical testing.