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Antimicrobial Agents and Chemotherapy, August 2002, p. 2381-2386, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2381-2386.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Alkoxyalkyl Esters of Cidofovir and Cyclic Cidofovir Exhibit Multiple-Log Enhancement of Antiviral Activity against Cytomegalovirus and Herpesvirus Replication In Vitro

James R. Beadle,1 Caroll Hartline,2 Kathy A. Aldern,1 Natalie Rodriguez,1 Emma Harden,2 Earl R. Kern,2 and Karl Y. Hostetler1*

Department of Medicine, Veterans Affairs Medical Center, and the University of California, San Diego, La Jolla, California 92093-0676,1 Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama 35294-21702

Received 16 November 2001/ Returned for modification 5 February 2002/ Accepted 18 April 2002

The incidence of cytomegalovirus (CMV) retinitis is declining in AIDS patients but remains a significant clinical problem in patients with organ transplants and bone marrow transplants. Prophylaxis with ganciclovir (GCV) or valganciclovir reduces the incidence of CMV disease but may lead to the emergence of drug-resistant virus with mutations in the UL97 or UL54 gene. It would be useful to have other types of oral therapy for CMV disease. We synthesized hexadecyloxypropyl and octadecyloxyethyl derivatives of cyclic cidofovir (cCDV) and cidofovir (CDV) and found that these novel analogs had 2.5- to 4-log increases in antiviral activity against CMV compared to the activities of unmodified CDV and cCDV. Multiple-log increases in activity were noted against laboratory CMV strains and various CMV clinical isolates including GCV-resistant strains with mutations in the UL97 and UL54 genes. Preliminary cell studies suggest that the increase in antiviral activity may be partially explained by a much greater cell penetration of the novel analogs. 1-O-Hexadecyloxypropyl-CDV, 1-O-octadecyloxyethyl-CDV, and their corresponding cCDV analogs are worthy of further preclinical evaluation for treatment and prevention of CMV and herpes simplex virus infections in humans.

* Corresponding author. Mailing address: Department of Medicine (0676), University of California, 305 Clinical Sciences Building, 9500 Gilman Dr., San Diego, La Jolla, CA 92093-0676. Phone: (858) 552-8585, ext. 2616. Fax: (858) 534-6133. E-mail: khostetl{at}ucsd.edu.

Antimicrobial Agents and Chemotherapy, August 2002, p. 2381-2386, Vol. 46, No. 8
0066-4804/02/$04.00+0     DOI: 10.1128/AAC.46.8.2381-2386.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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