WEISS WJ, DIGRANDI M, BLOOM J, VISALLI R; Interscience Conference on Antimicrobial Agents and Chemotherapy; V.Z.V. PRECLINICAL DEVELOPMENT TEAM.
Abstr Intersci Conf Antimicrob Agents Chemother Intersci Conf Antimicrob Agents Chemother. 2000 Sep 17-20; 40: 264.
Wyeth-Ayerst Res., Pearl River, NY
Varicella zoster virus (VZV) causes a disseminated primary infection known as chickenpox and, at a later date, may reactivate to cause herpes zoster, more commonly known as ``shingles. The persistent pain (Post-Herpetic Neuralgia) that often follows healing of the zoster-associated rash is of major concern clinically. Potent anti-VZV compounds able to penetrate to the site of reactivation and inhibit virus replication may be able to alter the prevalence and duration of PHN. A series of non-nucleoside analogs were synthesized which demonstrated activity against VZV. A total of 80 compounds exhibited IC50 values of less than 1 microg/ml (ranging from 0.01 to 1 microg/ml) by ELISA. They were shown to be inactive against other herpesviruses (HSV1, HSV2 and HCMV) and exhibited no cytotoxicity by MTS assay (therapeutic index greater than 100-fold in growing cells). The compound series was active against our VZV laboratory strain Ellen, VZV clinical strains, and an acyclovir resistant VZV isolate. Select compounds were orally bio-available in mice, rats, dogs and monkeys. Serum levels in monkeys (single oral dose) were above the IC50 for > 12 hours indicating that once or twice-a-day dosing may be effective. The compounds exhibited excellent tissue distribution (> 1.5 L/kg) and half-life (2.6-7 hrs) after intravenous administration in primates. The inhibitors were well tolerated after both single and multiple oral dosing studies in mice and monkeys. The potent in vitro activity coupled with the favorable pharmacokinetics of these compounds warrant further investigation for treatment of VZV infections.KEYWORDS: Herpesvirus; Pharmacokinetics; VZV
Publication Types:
Keywords:
- Acyclovir
- Animals
- Antiviral Agents
- Chickenpox
- Cytomegalovirus
- Dogs
- Haplorhini
- Herpes Zoster
- Herpesviridae
- Herpesviridae Infections
- Herpesvirus 3, Human
- In Vitro
- Mice
- Motor Activity
- Neuralgia
- Rats
- Simplexvirus
- Virus Replication
- pharmacokinetics
- virology
Other ID:
UI: 102246945
From Meeting Abstracts