Synthesis and anti-HIV activity of GS-9148 (2′-Fd4AP), a novel nucleoside phosphonate HIV reverse transcriptase inhibitor

GS-9148 (2′-Fd4AP, 4) has been identified as a nucleoside phosphonate reverse transcriptase (RT) inhibitor with activity against wild-type HIV (EC50 = 12 μM). Unlike many clinical RT inhibitors, relevant reverse transcriptase mutants (M184V, K65R, 6-TAMs) maintain a susceptibility to 2′-Fd4AP that is similar to wild-type virus. The 2′-fluorine group was rationally designed into the molecule to improve the selectivity profile and in preliminary studies using HepG2 cells, compound 4 showed no measurable effect on mitochondrial DNA content indicating a low potential for mitochondrial toxicity.

Graphical abstractCompound 4 (2′-Fd4AP) was synthesized and maintained the favorable anti-HIV properties of 2 while demonstrating a marked reduction in mitochondrial toxicity to HepG2 cells.Figure optionsDownload full-size imageDownload as PowerPoint slide