Fluorescent bicyclic furo pyrimidine deoxynucleoside analogs as potent
                        and selective inhibitors of VZV and potential future drugs for the treatment
                        of chickenpox and shingles

McGuigan, Christopher; Brancale, Andrea; Barucki, Hubert; Srinivasan, Suseela; Jones, Garry; Pathirana, Ranjith; Blewett, Sally; Álvarez, Raquel; Yarnold, Christopher J.; Carangio, Antonella; Velázquez, Sonsoles; Andrei, Gracíela; Snoeck, Robert; Clercq, Erik De; Balzarini, Jan

doi:10.1358/dof.2000.025.11.858698

Cited by 37 publications

(48 citation statements)

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“…The prodrug FV-100 and its major active metabolite, CF-1743, represent a new class of nucleoside analogues with a novel bicyclic pyrimidine base bearing a long alkyl or p-alkylphenyl side chain (9,10). Their rapid intracellular uptake and strong in vivo inhibition of laboratory VZV strains as well as clinical VZV isolates at concentrations in the low nanomolar range may present a novel approach to the unmet clinical challenges in the treatment of HZ and prevention of PHN (1,9,10,11,12).…”

Section: Discussionmentioning

confidence: 99%

“…Their rapid intracellular uptake and strong in vivo inhibition of laboratory VZV strains as well as clinical VZV isolates at concentrations in the low nanomolar range may present a novel approach to the unmet clinical challenges in the treatment of HZ and prevention of PHN (1,9,10,11,12).…”

Section: Discussionmentioning

confidence: 99%

“…After a pilot study in which human subjects received single low oral doses (10,20, and 40 mg) of FV-100 and in which FV-100 exhibited a favorable safety profile, 3 additional studies were conducted from April 2008 to January 2009 to more fully characterize the pharmacokinetics and evaluate the safety of potential therapeutic doses of FV-100. These randomized, double-blind, placebo-controlled clinical trials were conducted in accordance with good clinical practices, the Declaration of Helsinki (October 2000), and United States Food and Drug Administration regulations, as codified in the Code of Federal Regulations, Title 21, including approval of the protocol and written informed consent form by an institutional review board before study initiation and the collection of informed consent prior to screening of each subject.…”

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confidence: 99%

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Pharmacokinetics and Safety of FV-100, a Novel Oral Anti-Herpes Zoster Nucleoside Analogue, Administered in Single and Multiple Doses to Healthy Young Adult and Elderly Adult Volunteers

Pentikis¹,

Matson

Atiee³

et al. 2011

Antimicrob Agents Chemother

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FV-100 is the prodrug of the highly potent anti-varicella zoster virus bicyclic nucleoside analogue CF-1743. To characterize the pharmacokinetics and safety of oral FV-100, 3 randomized, double-blind, placebo-controlled clinical trials were conducted: (i) a single-ascending-dose study in 32 healthy subjects aged 18 to 55 years (100-, 200-, 400-, and 800-mg doses) with an evaluation of the food effect in the 400-mg group; (ii) a multiple-ascending-dose study in 48 subjects aged 18 to 55 years (100 mg once daily [QD], 200 mg QD, 400 mg QD, 400 mg twice a day, and 800 mg QD for 7 days); and (iii) a 2-part study in subjects aged 65 years and older with a single 400-mg dose in 15 subjects and a 400-mg QD dosing regimen for 7 days in 12 subjects. FV-100 was rapidly and extensively converted to CF-1743, the concentration of which remained above that required to reduce viral activity by 50% for the 24-hour dosing period. Renal excretion of CF-1743 was very low. A high-fat meal reduced exposure to CF-1743; a low-fat meal did not. Pharmacokinetic parameters for the elderly subjects were comparable to those for the younger subjects. FV-100 was well tolerated by all subjects. The pharmacokinetic and safety profiles of FV-100 support its continued investigation for the treatment of herpes zoster and prevention of postherpetic neuralgia with once-daily dosing and without dose modifications for elderly or renally impaired patients.Herpes zoster (HZ), or shingles, is a painful rash caused by varicella zoster virus (VZV) infection of peripheral nerves. It has the highest incidence of all neurological diseases, with over 1 million cases developing annually in the United States (5, 8). The Centers for Disease Control and Prevention reports that 32% of people in the United States will experience zoster during their lifetimes, and as many as 50% of those living until 85 years of age will develop shingles (5, 14).HZ is caused by the reactivation of latent VZV residing in ganglia in persons with prior chicken pox with subsequent spread to the peripheral nerves. While the acute rash generally heals within 2 to 4 weeks, the most distressing symptom of HZ is pain, both acute and chronic. Chronic pain associated with HZ infection is also referred to as postherpetic neuralgia (PHN), a clinically significant condition that can last from several months to years. Several clinical trials of antiviral medications now approved for the treatment of HZ as well as meta-analyses have shown a reduction in acute pain and PHN with antiviral medication treatment compared to placebo (7,8,15). However, 22% of all patients with HZ still develop PHN (2), and thus, existing interventions, including vaccination and analgesia as well as currently approved antivirals, do not completely prevent or adequately treat all cases of HZ pain and PHN (4,6,13,16). Development of more effective compounds for the prevention and treatment of HZ-associated pain is an unmet medical need (3).A number of in vitro tests were conducted to evaluate the potential toxicity of FV-100...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Pharmacokinetics and Safety of FV-100, a Novel Oral Anti-Herpes Zoster Nucleoside Analogue, Administered in Single and Multiple Doses to Healthy Young Adult and Elderly Adult Volunteers

Pentikis¹,

Matson

Atiee³

et al. 2011

Antimicrob Agents Chemother

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“…The BCNAs were synthesized as described previously (McGuigan et al, 1999(McGuigan et al, , 2000b. The synthesis of the 5Ј-monophosphates of Cf 1368 and Cf 1369, which were called Cf 1928 and Cf 1602, respectively ( Fig.…”

Section: Methodsmentioning

confidence: 99%

“…Recently, side-chain modifications [i.e., terminal halogen substitution (Brancale et al, 2000), terminal unsaturation , and pyrro and thieno substitutions (McGuigan et al, 2000c] were conducted to clarify the role of the hydrophobic side chain and further optimize the lead compounds. Cf 1743, bearing a p-pentylphenyl as the side chain, has been identified as the most active anti-VZV compound (EC 50 ϭ 0.0003 M) in cell culture and is at least 3000 times more active against VZV in cell culture than is the clinically used ACV (EC 50 ϭ 1 M) (McGuigan et al, 2000b).…”

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confidence: 99%

Specific Recognition of the Bicyclic Pyrimidine Nucleoside Analogs, a New Class of Highly Potent and Selective Inhibitors of Varicella-Zoster Virus (VZV), by the VZV-Encoded Thymidine Kinase

et al. 2002

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Recently, an entirely new class of bicyclic nucleoside analogs (BCNAs) was found to display exquisite potency and selectivity as inhibitors of varicella-zoster virus (VZV) replication in cell culture. A striking difference in their ability to convert the BCNAs to their phosphorylated derivatives was observed between the VZV-encoded thymidine kinase (TK) and the very closely related herpes simplex virus type 1 (HSV-1) TK. Whereas VZV TK efficiently phosphorylated the BCNAs, HSV-1 TK was unable to do so. In addition, the thymidylate (dTMP) kinase activity of VZV TK further converted BCNA-5Ј-MP to BCNA-5Ј-DP. The BCNAs (or their phosphorylated derivatives) were not a substrate for cytosolic TK, mitochondrial TK, or cytosolic dTMP kinase. Human erythrocyte nucleoside diphosphate (NDP) kinase was unable to phosphorylate the BCNA 5Ј-diphosphates to BCNA 5Ј-triphosphates. Under the same experimental conditions, the anti-herpetic (E)-5-(2-bromovinyl)-2Ј-deoxyuridine (BVDU) derivative was efficiently converted to BVDU-MP and BVDU-DP by both VZV TK and HSV-1 TK and further, into BVDU-TP, by NDP kinase. Our observations may account for the unprecedented specificity of BCNAs as anti-VZV agents.

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Synthesis of Furo[2,3‐b]pyrazine Nucleoside Analogues with 1,2,3‐Triazole Linkage

2007

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Sonogashira coupling reaction with the readily available 1-(4-methoxybenzyl)-3,5-dichloropyrazin-2(1H)-ones was followed by mild silver-catalyzed cyclization to provide the corresponding 2-chlorofuro[2,3-b]pyrazines in excellent yields. A second Sonogashira cross-coupling reaction resulted in the formation of 2-ethynylfuro[2,3-b]pyrazines, which were coupled with d-ribose and 2-deoxy-d-ribose using a microwave-assisted Cu(I)-catalyzed Huisgen [2 þ 3] dipolar cycloaddition reaction, to generate a small library of new nucleoside analogues.

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Fluorescent bicyclic furo pyrimidine deoxynucleoside analogs as potent and selective inhibitors of VZV and potential future drugs for the treatment of chickenpox and shingles

Cited by 37 publications

References 0 publications

Pharmacokinetics and Safety of FV-100, a Novel Oral Anti-Herpes Zoster Nucleoside Analogue, Administered in Single and Multiple Doses to Healthy Young Adult and Elderly Adult Volunteers

Pharmacokinetics and Safety of FV-100, a Novel Oral Anti-Herpes Zoster Nucleoside Analogue, Administered in Single and Multiple Doses to Healthy Young Adult and Elderly Adult Volunteers

Specific Recognition of the Bicyclic Pyrimidine Nucleoside Analogs, a New Class of Highly Potent and Selective Inhibitors of Varicella-Zoster Virus (VZV), by the VZV-Encoded Thymidine Kinase

Synthesis of Furo[2,3‐b]pyrazine Nucleoside Analogues with 1,2,3‐Triazole Linkage

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