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

2007; Elsevier BV; Volume: 18; Issue: 3 Linguagem: Inglês

10.1016/j.bmcl.2007.11.125

1464-3405

Constantine G. Boojamra, Richard L. Mackman, David Y. Markevitch, Vidya Prasad, Adrian S. Ray, Janet L. Douglas, Deborah Grant, Choung U. Kim, Tomáš Cihlář,

Pneumocystis jirovecii pneumonia detection and treatment

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.