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

Constantine G. Boojamra; Richard L. Mackman; David Y. Markevitch; Vidya Prasad; Adrian S. Ray; Janet Douglas; Deborah Grant; Choung U. Kim; Tomas Cihlar

doi:10.1016/j.bmcl.2007.11.125

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

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

Research output: Contribution to journal › Article › peer-review

56 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	1120-1123
Number of pages	4
Journal	Bioorganic and Medicinal Chemistry Letters
Volume	18
Issue number	3
DOIs	https://doi.org/10.1016/j.bmcl.2007.11.125
State	Published - Feb 1 2008
Externally published	Yes

Keywords

Antiviral
HIV
Phosphonate
Resistance

ASJC Scopus subject areas

Biochemistry
Molecular Medicine
Molecular Biology
Pharmaceutical Science
Drug Discovery
Clinical Biochemistry
Organic Chemistry

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10.1016/j.bmcl.2007.11.125

Cite this

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abstract = "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.",

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AU - Boojamra, Constantine G.

AU - Mackman, Richard L.

AU - Markevitch, David Y.

AU - Prasad, Vidya

AU - Ray, Adrian S.

AU - Douglas, Janet

AU - Grant, Deborah

AU - Kim, Choung U.

AU - Cihlar, Tomas

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Y1 - 2008/2/1

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AB - 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.

KW - Antiviral

KW - HIV

KW - Phosphonate

KW - Resistance

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

Abstract

Keywords

ASJC Scopus subject areas

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