Phosphorodiamidates as a Promising New Phosphate Prodrug Motif for Antiviral Drug Discovery: Application to Anti-HCV Agents

McGuigan, Christopher; Madela, Karolina; Aljarah, Mohamed; Bourdin, Claire; Arrica, Maria A.; Barrett, Emma; Jones, Sarah L.; Kolykhalov, Alexander A.; Bleiman, Blair; Bryant, K. Dawn; Ganguly, Babita; Gorovits, Elena L.; Henson, Geoffrey; Hunley, Damound; Hutchins, Jeff; Muhammad, Jerry; Obikhod, Aleksandr; Patti, Joseph M.; Walters, C. Robin; Wang, Jin; Vernachio, John; Ramamurty, Changalvala V. S.; Battina, Srinivas K.; Chamberlain, Stanley D.

doi:10.1021/jm2011673

Cited by 48 publications

(62 citation statements)

References 29 publications

(102 reference statements)

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“…GS-465124 is a nucleotide phosphoramidate, and the metabolic activation of this type of prodrug when applied to different nucleotide analogs has been characterized (18)(19)(20). Similar to the other phosphoramidate prodrugs targeting HCV, including sofosbuvir (GS-7977) and PSI-353661, GS-465124 was hydrolyzed by CES1 and CatA to form metabolite X, followed by HINT1-mediated removal of L-alanine resulting in the formation of the nucleoside analog monophosphate, GS-558272 (8, 9).…”

Section: Discussionmentioning

confidence: 99%

Metabolism and Pharmacokinetics of the Anti-Hepatitis C Virus Nucleotide Prodrug GS-6620

Murakami

Wang

Babusis

et al. 2014

Antimicrob Agents Chemother

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The anti-hepatitis C virus nucleotide prodrug GS-6620 employs a double-prodrug approach, with L-alanine-isopropyl ester and phenol moieties attached to the 5=-phosphate that release the nucleoside monophosphate in hepatocytes and a 3=-isobutyryl ester added to improve permeability and oral bioavailability. Consistent with the stability found in intestinal homogenates, following oral administration, intact prodrug levels in blood plasma were the highest in dogs, followed by monkeys, and then were the lowest in hamsters. In contrast, liver levels of the triphosphate metabolite at the equivalent surface area-adjusted doses were highest in hamsters, followed by in dogs and monkeys. Studies in isolated primary hepatocytes suggest that relatively poor oral absorption in hamsters and monkeys was compensated for by relatively efficient hepatocyte activation. As intestinal absorption was found to be critical to the effectiveness of GS-6620 in nonclinical species, stomach pH, formulation, and food effect studies were completed in dogs. Consistent with in vitro absorption studies in Caco-2 cells, the absorption of GS-6620 was found to be complex and highly dependent on concentration. Higher rates of metabolism were observed at lower concentrations that were unable to saturate intestinal efflux transporters. In first-in-human clinical trials, the oral administration of GS-6620 resulted in poor plasma exposure relative to that observed in dogs and in large pharmacokinetic and pharmacodynamic variabilities. While a double-prodrug approach, including a 3=-isobutyryl ester, provided higher intrinsic intestinal permeability, this substitution appeared to be a metabolic liability, resulting in extensive intestinal metabolism and relatively poor oral absorption in humans.A pproximately 170 million people worldwide are infected by the hepatitis C virus (HCV), and nearly 2% of the U.S. population is estimated to have HCV (1). HCV is a major health issue since approximately 15 to 35% of those who are chronically infected will develop cirrhosis and 1 to 3% will progress to hepatocellular carcinoma over 30 years (2). Currently, the recently approved protease inhibitors (boceprevir and telaprevir) are used in combination with pegylated interferon alpha plus ribavirin (PEG-RBV) for the treatment of chronic HCV infection. While these treatments show improved response rates and the potential for shorter duration of treatment over PEG-RBV alone, they lack efficacy against genotypes other than genotype 1, require thricedaily dosing, and cause additional side effects from the new directacting antivirals on top of the already-challenging tolerability profile of PEG-RBV. Therefore, there is a need for more potent anti-HCV compounds with improved clinical efficacy and greater tolerability in order to more broadly address the unmet medical needs of those with chronic HCV infection. Combinations of antiviral agents targeting viral proteins essential to HCV replication have the potential to achieve increased clinical efficacy across HCV genotypes, ...

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Section: Discussionmentioning

confidence: 99%

Metabolism and Pharmacokinetics of the Anti-Hepatitis C Virus Nucleotide Prodrug GS-6620

Murakami

Wang

Babusis

et al. 2014

Antimicrob Agents Chemother

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“…A putative mechanism of unmasking to the monophosphate was proposed by McGuigan et al 255 in which carboxypeptidase cleaves the ester function of the amino acid, inducing spontaneous cyclization of the carboxylate of the free amino acid onto the phosph(on)ate moiety. After a spontaneous hydrolysis, the nucleoside phosphoramidate monoester is cleaved into the free nucleoside monophosph(on)ate by action of phosphoramidase (Figure 45).…”

Section: Nucleoside Monophosphate Prodrugsmentioning

confidence: 99%

“…255 Compounds were prepared either using the conditions described above or by slight modification of the procedure. Nucleoside was first phosphorylated with POCl 3 at −78 °C in THF.…”

Section: Nucleoside Monophosphate Prodrugsmentioning

confidence: 99%

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

et al. 2014

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“…33,34,35 In our SAR-study, the ethyl ester of the natural amino acid, L-phenylalanine, was selected to mask both phosphonate groups of our inhibitors. 36,37 This type of prodrug is more stable than ester prodrugs. In solution no hydrolysis was observed at pH 7.…”

Section: Chemistrymentioning

confidence: 99%

Synthesis and evaluation of symmetric acyclic nucleoside bisphosphonates as inhibitors of the Plasmodium falciparum, Plasmodium vivax and human 6-oxopurine phosphoribosyltransferases and the antimalarial activity of their prodrugs

Špaček

Keough

Chavchich³

et al. 2017

Bioorganic & Medicinal Chemistry

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Abstract:Two new series of symmetric acyclic nucleoside bisphosphonates (ANbPs) have been synthesised as potential inhibitors of the Plasmodium falciparum (Pf) and vivax (Pv) 6-oxopurine phosphoribosyltransferases. The structural variability between these symmetric ANbPs lies in the number of atoms in the two acyclic linkers connecting the N 9 atom of the purine base to each of two phosphonate groups and the branching point of the acyclic moiety relative to the purine base, which occurs at either the alpha or beta positions. Within each series, six different 6-oxopurine bases have been attached. In general, the ANbPs with either guanine or hypoxanthine have lower K i values than for those containing either the 8-bromo or 7-deaza 6-oxopurine bases. The lowest K i values obtained for the two parasite enzymes were 0.1 µM (Pf) and 0.2 µM (Pv) for this series of compounds. Two phosphoramidate prodrugs of these inhibitors exhibited antimalarial activity against Pf in infected erythrocyte cell culture 2 with IC 50 values of 0.8 and 1.5 µM. These two compounds exhibited low cytotoxicity in human A549 cells having CC 50 values of >300 µM resulting in an excellent selectivity index.

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Phosphorodiamidates as a Promising New Phosphate Prodrug Motif for Antiviral Drug Discovery: Application to Anti-HCV Agents

Cited by 48 publications

References 29 publications

Metabolism and Pharmacokinetics of the Anti-Hepatitis C Virus Nucleotide Prodrug GS-6620

Metabolism and Pharmacokinetics of the Anti-Hepatitis C Virus Nucleotide Prodrug GS-6620

Synthesis of Nucleoside Phosphate and Phosphonate Prodrugs

Synthesis and evaluation of symmetric acyclic nucleoside bisphosphonates as inhibitors of the Plasmodium falciparum, Plasmodium vivax and human 6-oxopurine phosphoribosyltransferases and the antimalarial activity of their prodrugs

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