Application of phosphoramidate pronucleotide technology to abacavir leads to a significant enhancement of antiviral potency

Christopher McGuigan; Sarah Knaggs; Susan M Daluge; Kristjan S Gudmundsson; Ed W McLean; Thimysta C Burnette; Harry Marr; Richard Hazen; Lynn D Condreay; Lance Johnson; Erik De Clercq; Jan Balzarini

doi:10.1021/jm0491400

Application of phosphoramidate pronucleotide technology to abacavir leads to a significant enhancement of antiviral potency

Christopher McGuigan, Sarah Knaggs, Susan M Daluge, Kristjan S Gudmundsson, Ed W McLean, Thimysta C Burnette, Harry Marr, Richard Hazen, Lynn D Condreay, Lance Johnson, Erik De Clercq, Jan Balzarini

Dentistry

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Abstract

We report the first application of pronucleotide (ProTide) technology to the antiviral agent abacavir (Ziagen), used for the treatment of HIV infection. The phenylmethoxyalaninyl phosphoramidate of abacavir was prepared in good yield in one step. Also prepared was the corresponding phosphoramidate of the guanine nucleoside analogue "carbovir". The antiviral profile of each of the parent nucleosides was compared to that of the phosphoramidate ProTides. A significant (28- to 60-fold) increase in anti-HIV potency was noted for the ProTide of abacavir but not for that of carbovir. These findings were in agreement with the markedly higher (ca. 37-fold) levels of carbovir triphosphate that are formed in CEM cells upon response to the abacavir ProTide compared with the parent abacavir compound. In contrast the anti-HBV potency of both abacavir and carbovir were improved (10- and 20-fold, respectively) by ProTide formation. As in CEM cells, the abacavir ProTide provided significantly enhanced carbovir triphosphate levels in HepG2 2.2.15 cells over that of the parent nucleoside. On the basis of these data, a series of phosphoramidate analogues with structural variation in the ester and amino acid regions were prepared and their antiviral profiles described. In addition, the pharmacokinetic disposition of the abacavir phenylethoxyalaninyl phosphoramidate was evaluated in Cynomolgus monkeys.

Original language	English
Pages (from-to)	3504-15
Number of pages	12
Journal	Journal of Medicinal Chemistry
Volume	48
Issue number	10
DOIs	https://doi.org/10.1021/jm0491400
Publication status	Published - 2005

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10.1021/jm0491400

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McGuigan, C., Knaggs, S., Daluge, S. M., Gudmundsson, K. S., McLean, E. W., Burnette, T. C., Marr, H., Hazen, R., Condreay, L. D., Johnson, L., De Clercq, E., & Balzarini, J. (2005). Application of phosphoramidate pronucleotide technology to abacavir leads to a significant enhancement of antiviral potency. Journal of Medicinal Chemistry, 48(10), 3504-15. https://doi.org/10.1021/jm0491400

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title = "Application of phosphoramidate pronucleotide technology to abacavir leads to a significant enhancement of antiviral potency",

abstract = "We report the first application of pronucleotide (ProTide) technology to the antiviral agent abacavir (Ziagen), used for the treatment of HIV infection. The phenylmethoxyalaninyl phosphoramidate of abacavir was prepared in good yield in one step. Also prepared was the corresponding phosphoramidate of the guanine nucleoside analogue {"}carbovir{"}. The antiviral profile of each of the parent nucleosides was compared to that of the phosphoramidate ProTides. A significant (28- to 60-fold) increase in anti-HIV potency was noted for the ProTide of abacavir but not for that of carbovir. These findings were in agreement with the markedly higher (ca. 37-fold) levels of carbovir triphosphate that are formed in CEM cells upon response to the abacavir ProTide compared with the parent abacavir compound. In contrast the anti-HBV potency of both abacavir and carbovir were improved (10- and 20-fold, respectively) by ProTide formation. As in CEM cells, the abacavir ProTide provided significantly enhanced carbovir triphosphate levels in HepG2 2.2.15 cells over that of the parent nucleoside. On the basis of these data, a series of phosphoramidate analogues with structural variation in the ester and amino acid regions were prepared and their antiviral profiles described. In addition, the pharmacokinetic disposition of the abacavir phenylethoxyalaninyl phosphoramidate was evaluated in Cynomolgus monkeys.",

author = "Christopher McGuigan and Sarah Knaggs and Daluge, {Susan M} and Gudmundsson, {Kristjan S} and McLean, {Ed W} and Burnette, {Thimysta C} and Harry Marr and Richard Hazen and Condreay, {Lynn D} and Lance Johnson and {De Clercq}, Erik and Jan Balzarini",

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doi = "10.1021/jm0491400",

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journal = "Journal of Medicinal Chemistry",

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McGuigan, C, Knaggs, S, Daluge, SM, Gudmundsson, KS, McLean, EW, Burnette, TC, Marr, H, Hazen, R, Condreay, LD, Johnson, L, De Clercq, E & Balzarini, J 2005, 'Application of phosphoramidate pronucleotide technology to abacavir leads to a significant enhancement of antiviral potency', Journal of Medicinal Chemistry, vol. 48, no. 10, pp. 3504-15. https://doi.org/10.1021/jm0491400

TY - JOUR

T1 - Application of phosphoramidate pronucleotide technology to abacavir leads to a significant enhancement of antiviral potency

AU - McGuigan, Christopher

AU - Knaggs, Sarah

AU - Daluge, Susan M

AU - Gudmundsson, Kristjan S

AU - McLean, Ed W

AU - Burnette, Thimysta C

AU - Marr, Harry

AU - Hazen, Richard

AU - Condreay, Lynn D

AU - Johnson, Lance

AU - De Clercq, Erik

AU - Balzarini, Jan

PY - 2005

Y1 - 2005

N2 - We report the first application of pronucleotide (ProTide) technology to the antiviral agent abacavir (Ziagen), used for the treatment of HIV infection. The phenylmethoxyalaninyl phosphoramidate of abacavir was prepared in good yield in one step. Also prepared was the corresponding phosphoramidate of the guanine nucleoside analogue "carbovir". The antiviral profile of each of the parent nucleosides was compared to that of the phosphoramidate ProTides. A significant (28- to 60-fold) increase in anti-HIV potency was noted for the ProTide of abacavir but not for that of carbovir. These findings were in agreement with the markedly higher (ca. 37-fold) levels of carbovir triphosphate that are formed in CEM cells upon response to the abacavir ProTide compared with the parent abacavir compound. In contrast the anti-HBV potency of both abacavir and carbovir were improved (10- and 20-fold, respectively) by ProTide formation. As in CEM cells, the abacavir ProTide provided significantly enhanced carbovir triphosphate levels in HepG2 2.2.15 cells over that of the parent nucleoside. On the basis of these data, a series of phosphoramidate analogues with structural variation in the ester and amino acid regions were prepared and their antiviral profiles described. In addition, the pharmacokinetic disposition of the abacavir phenylethoxyalaninyl phosphoramidate was evaluated in Cynomolgus monkeys.

AB - We report the first application of pronucleotide (ProTide) technology to the antiviral agent abacavir (Ziagen), used for the treatment of HIV infection. The phenylmethoxyalaninyl phosphoramidate of abacavir was prepared in good yield in one step. Also prepared was the corresponding phosphoramidate of the guanine nucleoside analogue "carbovir". The antiviral profile of each of the parent nucleosides was compared to that of the phosphoramidate ProTides. A significant (28- to 60-fold) increase in anti-HIV potency was noted for the ProTide of abacavir but not for that of carbovir. These findings were in agreement with the markedly higher (ca. 37-fold) levels of carbovir triphosphate that are formed in CEM cells upon response to the abacavir ProTide compared with the parent abacavir compound. In contrast the anti-HBV potency of both abacavir and carbovir were improved (10- and 20-fold, respectively) by ProTide formation. As in CEM cells, the abacavir ProTide provided significantly enhanced carbovir triphosphate levels in HepG2 2.2.15 cells over that of the parent nucleoside. On the basis of these data, a series of phosphoramidate analogues with structural variation in the ester and amino acid regions were prepared and their antiviral profiles described. In addition, the pharmacokinetic disposition of the abacavir phenylethoxyalaninyl phosphoramidate was evaluated in Cynomolgus monkeys.

U2 - 10.1021/jm0491400

DO - 10.1021/jm0491400

M3 - Article

C2 - 15887959

SN - 0022-2623

VL - 48

SP - 3504

EP - 3515

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 10

ER -

Application of phosphoramidate pronucleotide technology to abacavir leads to a significant enhancement of antiviral potency

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