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Antimicrobial Agents and Chemotherapy, August 2002, p. 2373-2380, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2373-2380.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Preclinical and Toxicology Studies of 1263W94, a Potent and Selective Inhibitor of Human Cytomegalovirus Replication

George W. Koszalka,1 Nelson W. Johnson,1 Steven S. Good,1 Leslie Boyd,1 Stanley C. Chamberlain,1 Leroy B. Townsend,2 John C. Drach,2 and Karen K. Biron1*

GlaxoSmithKline, Research Triangle Park, North Carolina 27709,1 College of Pharmacy and School of Dentistry, University of Michigan, Ann Arbor, Michigan 481092

Received 31 August 2001/ Returned for modification 4 December 2001/ Accepted 18 April 2002

1263W94 is a novel benzimidazole compound being developed for treatment of human cytomegalovirus infection. No adverse pharmacological effects were demonstrated in safety pharmacology studies with 1263W94. The minimal-effect dose in a 1-month rat study was 100 mg/kg/day, and the no-effect dose in a 1-month monkey study was 180 mg/kg/day. Toxic effects were limited to increases in liver weights, neutrophils, and monocytes at higher doses in female rats. 1263W94 was not genotoxic in the Ames or micronucleus assays. In the mouse lymphoma assay, 1263W94 was mutagenic in the absence of the rat liver S-9 metabolic activation system, with equivocal results in the presence of the S-9 mix. Mean oral bioavailability of 1263W94 was >90% in rats and ~50% in monkeys. Clearance in rats and monkeys was primarily by biliary secretion, with evidence of enterohepatic recirculation. In 1-month studies in rats and monkeys, mean peak concentrations and exposures to 1263W94 increased in near proportion to dose. Metabolism of 1263W94 to its primary metabolite, an N-dealkylated analog, appeared to be mediated via the isozyme CYP3A4 in humans. 1263W94 was primarily distributed in the gastrointestinal tract of rats but did not cross the blood-brain barrier. In monkeys, 1263W94 levels in the brain, cerebrospinal fluid, and vitreous humor ranged from 4 to 20%, 1 to 2%, and <1%, of corresponding concentrations in plasma, respectively. The high level of binding by 1263W94 to human plasma proteins (primarily albumin) was readily reversible, with less protein binding seen in the monkey, rat, and mouse. Results of these studies demonstrate a favorable safety profile for 1263W94.

* Corresponding author. Mailing address: GlaxoSmithKline, 5 Moore Dr., Research Triangle Park, NC 27709. Phone: (919) 483-9310. Fax: (919) 315-5243. E-mail: kkb21173{at}gsk.com.

Antimicrobial Agents and Chemotherapy, August 2002, p. 2373-2380, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2373-2380.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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