Synthesis and Antiviral Evaluation of Carbocyclic Nucleoside Analogs of Nucleoside Reverse Transcriptase Translocation Inhibitor MK-8591 (4′-Ethynyl-2-fluoro-2′-deoxyadenosine)

MK-8591 (4′-ethynyl-2-fluoro-2′-deoxyadenosine)
is
a novel nucleoside analog that displays a differentiated mechanism
of action as a nucleoside reverse transcriptase translocation inhibitor
(NRTTI) compared to approved NRTIs. Herein, we describe our recent
efforts to explore the impact of structural changes to the properties
of MK-8591 through the synthesis and antiviral evaluation of carbocyclic
derivatives. Synthesized analogs were evaluated for their antiviral
activity, and the corresponding triphosphates were synthesized and
evaluated in a biochemical assay. 4′-Ethynyl-G derivative (±)-29 displayed a promising IC50 of 33 nM in a hPBMC
cell-based antiviral assay, and its triphosphate (TP), (±)-29-TP, displayed an IC50 of 324 nM
in a biochemical RT-polymerase assay. Improved TP anabolite delivery
resulting in improved in vitro potency was achieved by
preparing the corresponding phosphoramidate prodrug of single enantiomer 29b, with 6-ethoxy G derivative 34b displaying
a significantly improved IC50 of 3.0 nM, paving the way
for new directions for this novel class of nucleoside analogs.