Discovery of GS-9131: Design, synthesis and optimization of amidate prodrugs of the novel nucleoside phosphonate HIV reverse transcriptase (RT) inhibitor GS-9148

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

“…35 The conversion of nucleoside 458 into phosphonate intermediate 461 was accomplished by oxidation of the 5′-hydroxyl using Jones’ reagent, glycal formation under Mitsunobu conditions, and treatment with IBr and diphenyl hydroxymethyl phosphate. Oxidation of the iodine with NaOCl and treatment with aqueous ammonia afforded the nucleoside phenyl phosphonate monoester 462 in 18% yield.…”

“…A similar procedure was used by Mackman et al 35 for the synthesis of GS-9148 bis(amino acid) prodrug derivative (Scheme 169). Diethyl nucleoside phosphonate 544 was first treated with ammonium hydroxide generating 6-aminopurine nucleobase while deprotecting one of the phosphonate esters.…”

Reaction of Arylnitroso Derivatives: Synthesis of Arylimino 2,5-Dihydrofuran and Arylamino Fulvenes Derivatives

“…The interest on synthetic methodologies leading to 2,5-dihydrofuran and imino-2,5-dihydrofuran derivatives [13] is very considerable. These structures are subunit of several bioactive natural and synthetic products [14] [15]. Fulvenes have high relevance as synthons [16] [17] and materials [18]- [24].…”

The rationality for using prodrug approach in drug discovery programs for new xenobiotics: opportunities and challenges

“…These produgs had the ability to reduce the bacterial load both in urine and bladder by 2-4 orders of magnitude and has showed promise for an effective oral treatment (Klein et al 2010), (6) a diacetyl derivative of L-dopa amide was found to generate adequate plasma levels of L-dopa in vivo and among a number of other prodrug analogs synthesized it appeared that the diacetyl derivative of L-dopa was the most active in the unilaterally 6-hydroxydopamine-lesioned rat model for treating Parkinson's disease (Zhou et al 2010), (7) GS-9131 is an ethylalaninyl phosphonamidate prodrug which has been designed to specifically target intracellular cathepsin A, a lysosomal carboxypeptidase, for its activation. Upon activation by cathespsin A, GS-9148 ([(5-(6-amino-purine-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosphonic acid] is generated which is a novel HIV-1 reverse transcriptase inhibitor (Mackman et al 2010). The in vivo studies in dogs demonstrated proof of principle for the liberation of GS-9148 in peripheral blood mononuclear cells after dosing with the prodrug, GS-9131 (Mackman et al 2010), (8) to obtain a nanomolar inhibitor of catechol-O-methyltransferase inhibitor, a series of lipophilic esters were made (Rautio et al 2010).…”

“…Upon activation by cathespsin A, GS-9148 ([(5-(6-amino-purine-9-yl)-4-fluoro-2,5-dihydro-furan-2-yloxymethyl)phosphonic acid] is generated which is a novel HIV-1 reverse transcriptase inhibitor (Mackman et al 2010). The in vivo studies in dogs demonstrated proof of principle for the liberation of GS-9148 in peripheral blood mononuclear cells after dosing with the prodrug, GS-9131 (Mackman et al 2010), (8) to obtain a nanomolar inhibitor of catechol-O-methyltransferase inhibitor, a series of lipophilic esters were made (Rautio et al 2010). The optimization of various prodrugs to improve the oral bioavailability due to the low lipophilicity of the parent enabled the identification of a lead ester prodrug for further development (Rautio et al 2010).…”