Discovery of PSI-353661, a Novel Purine Nucleotide Prodrug for the Treatment of HCV Infection

Abstract

Hepatitis C virus afflicts approximately 180 million people worldwide, and the development of direct acting antivirals may offer substantial benefit compared to the current standard of care. Accordingly, prodrugs of 2'-deoxy-2'-fluoro-2'-C-methylguanosine monophosphate analogues were prepared and evaluated for their anti-HCV efficacy and tolerability. These prodrugs demonstrated >1000 fold greater potency than the parent nucleoside in a cell-based replicon assay as a result of higher intracellular triphosphate levels. Further optimization led to the discovery of the clinical candidate PSI-353661, which has demonstrated strong in vitro inhibition against HCV without cytotoxicity and equipotent activity against both the wild type and the known S282T nucleoside/tide resistant replicon. PSI-353661 is currently in preclinical development for the treatment of HCV.

Prodrugs of Phosphonates and Phosphates: Crossing the Membrane Barrier

“…The discovery of HIV stimulated tremendous efforts in this regard [59], and the continued importance of the disease encourages continued efforts in this area, including use of prodrugs such as tenofovir disoproxil as preventative agents [175]. Furthermore, increasing concern for viral infections such as HCV [100,135,176,177] and herpes virus [56] also motivates research. Because there are numerous reviews focused on prodrugs of nucleotides and nucleoside phosphonates [178–184], the following paragraphs focus primarily on other emerging applications in the nucleotide area.…”

Activity and the metabolic activation pathway of the potent and selective hepatitis C virus pronucleotide inhibitor PSI-353661

“…Therefore, phosphoramidate prodrug methodology was employed as an approach to bypass the non-productive first phosphorylation step and to intracellularly deliver 2′-deoxy-2′-α-fluoro-2′-β- C -methylguanosine 5′-monophosphate. Our subsequent work led to the identification of the phosphoramidate prodrug PSI-352879, (S)-2-{[(2R,3R,4R,5R)-5-(2-amino-6-methoxy-purin-9-yl)-4-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid isopropyl ester), which has potent activity in the HCV replicon assay (Chang et al, 2010). …”

“…PSI-352879 is a mixture of two diastereoisomers, of which PSI-353661 ((S)-2-{(S)- [(1R,4R,5R)-5-(2-Amino-6-methoxy-purin-9-yl)-4-(R)-fluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-phenoxy-phosphorylamino}-propionic acid isopropyl ester)) is the more active isomer in the replicon assay (Chang et al, 2010). Herein we describe the in vitro activity and metabolic pathway of the single isomer PSI-353661, a novel phosphoramidate prodrug of β- d -2′-deoxy-2′-α-fluoro-2′-β- C -methyl-6-methoxyguanosine-5′-monophosphate that has broad genotypic activity.…”

2′‐Fluoro‐6′‐methylene carbocyclic adenosine and its phosphoramidate prodrug: A novel anti‐HBV agent, active against drug‐resistant HBV mutants

“…The phosphoramidate prodrug method can bypass the rate‐limiting first step of monophosphorylation to increase the efficacy of synthetic nucleosides. A number of articles in the literature have described that the phosphoramidate prodrugs have improved the efficacy of nucleosides in cell culture, as well as in patients . In vivo, this methodology actually increases the lipophilicity of a nucleotide that allows easy and increased cell penetration to targeted cells (liver).…”