The acyclic nucleoside derivative HOE 602 (2-amino-9-[1,3-bis(isopropoxy)-2-propoxymethyl]purine) was evaluated for its antiviral activity in cell culture and for its therapeutic efficacy in mice infected with herpes simplex virus type 1 (HSV-1) and type 2 (HSV-2) or with murine cytomegalovirus (MCMV). HOE 602 was inactive in vitro against a variety of DNA- and RNA-viruses. However it prevented symptoms and mortality in mice systemically infected with HSV-1, HSV-2 or MCMV when administered intraperitoneally or orally at a dosage of 100 mumol/kg twice per day. Pharmacokinetic studies in mice and macaques revealed that HOE 602 was converted via three metabolic steps to ganciclovir, which seemed to be the antivirally active compound. The bioavailability of ganciclovir after oral administration of HOE 602 or ganciclovir was similar in mice, while in rhesus monkeys much higher serum levels of ganciclovir were reached with HOE 602. After intraperitoneal or intravenous administration higher drug levels were obtained with ganciclovir. The excellent therapeutic efficacy in animal models, the high enteral absorption in monkeys, and the favourable physical properties will hopefully lead to an orally active drug against cytomegalovirus and severe herpes infections in man.

01 Nov 1988·Arzneimittel-Forschung

New prodrugs of acyclic nucleosides with antiviral activity.

Article

Author: Jähne, G ; Rolly, H ; Rösner, M ; Winkelmann, E ; Winkler, I

More than 130 acyclic purine and pyrimidine nucleoside derivatives have been synthesized. Structure-activity relationships among a selected group of 6- and 9-substituted guanine derivatives will be discussed. By introduction of secondary aliphatic (e.g. isopropyl or secondary butyl) ether groups into acyclic nucleosides such as aciclovir and ganciclovir new lipophilic prodrugs with modified physical and improved pharmacokinetic properties have been obtained. Several compounds with isopropylether groups in the side-chain and/or in the 6-position (among these the 6-deoxy derivative Hoe 602) of the purine moiety displayed excellent antiviral activity when tested in vivo against herpes simplex virus type 1 infection in mice.

Arzneimittel-Forschung

New prodrugs of acyclic nucleosides with antiviral activity

Author: Jaehne, G. ; Winkelmann, E. ; Rolly, H. ; Roesner, M. ; Winkler, I.

More than 130 acyclic purine and pyrimidine nucleoside derivatives (I, R¹ = OH, OCHMe₂, or OCH₂CF₃, R² = H, CHMe₂ or Ac; and II, R² = OH, H, NH₂, or OCHMe₂, R² = OH, alkoxy, etc., R³ = H, OH, OAc, or OCHMe₂) was synthesized.Structure-activity relations among a selected group of 6- and 9-substituted guanine derivatives were discussed.By introduction of secondary aliphatic (e.g. iso-Pr or secondary butyl) ether groups into acyclic nucleosides, e.g., acyclovir and gancyclovir, new lipophilic prodrugs with modified phys. and improved pharmacokinetic properties were obtained.Several compounds with isopropyl ether groups in the side-chain and/or in the 6-position (among these the 6-deoxy derivative HOE 602) of the purine moiety displayed excellent antiviral activity when tested in vivo against herpes simplex virus type 1 infection in mice.

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Indication	Highest Phase	Country/Location	Organization	Date
Virus Diseases	Phase 1	-	Sanofi	-

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