This Article Full Text Full Text (PDF) An erratum has been published Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Reprints and Permissions Copyright Information Books from ASM Press MicrobeWorld Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Painter, G. R. Articles by Hostetler, K. Y. Search for Related Content PubMed PubMed Citation Articles by Painter, G. R. Articles by Hostetler, K. Y. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information AIDS Medicines Hepatitis B

 Previous Article  |  Next Article 

Antimicrobial Agents and Chemotherapy, October 2007, p. 3505-3509, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00460-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Evaluation of Hexadecyloxypropyl-9-R-[2-(Phosphonomethoxy)Propyl]- Adenine, CMX157, as a Potential Treatment for Human Immunodeficiency Virus Type 1 and Hepatitis B Virus Infections

George R. Painter,¹ Merrick R. Almond,¹ Lawrence C. Trost,¹ Bernhard M. Lampert,¹ Johan Neyts,² Erik De Clercq,² Brent E. Korba,³ Kathy A. Aldern,⁴ James R. Beadle,⁴ and Karl Y. Hostetler^4*

Chimerix Incorporated, 5007 Southpark Drive, Durham, North Carolina 27713,¹ Rega Institute for Medical Research, Faculty of Medicine, Katholieke Universiteit Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium,² Division of Molecular Virology and Immunology, Georgetown University Medical Center, Rockville, Maryland 20850,³ Veterans Medical Research Foundation and Department of Medicine, University of California, San Diego, La Jolla, California 92093-0676⁴

Received 3 April 2007/ Returned for modification 24 May 2007/ Accepted 12 July 2007

9-R-[2-(Phosphonomethoxy)propyl]-adenine (tenofovir) is an acyclic nucleoside phosphonate with antiviral activity against human immunodeficiency virus type 1 (HIV-1) and hepatitis B virus (HBV). Tenofovir is not orally bioavailable but becomes orally active against HIV-1 infection as the disoproxil ester (tenofovir disoproxil fumarate [Viread]). We have developed an alternative strategy for promoting the oral availability of nucleoside phosphonate analogs which involves esterification with a lipid to form a lysolecithin mimic. This mimic can utilize natural lysolecithin uptake pathways in the gut, resulting in high oral availability. Since the mimic is not subject to cleavage in the plasma by nonspecific esterases, it remains intact in the circulation and facilitates uptake by target cells. Significant drops in apparent antiviral 50% effective concentrations (EC₅₀s) of up to 3 logs have been observed in comparison with non-lipid-conjugated parent compounds in target cells. We have applied this technology to tenofovir with the goal of increasing oral availability, decreasing the apparent EC₅₀, and decreasing the potential for nephrotoxicity by reducing the exposure of the kidney to the free dianionic tenofovir. Here we report that, in vitro, the hexadecyloxypropyl ester of tenofovir, CMX157, is 267-fold more active than tenofovir against HIV-1 and 4.5-fold more active against HBV. CMX157 is orally available and has no apparent toxicity when given orally to rats for 7 days at doses of 10, 30, or 100 mg/kg/day. Consequently, CMX157 represents a second-generation tenofovir analog which may have an improved clinical profile.

---

* Corresponding author. Mailing address: Department of Medicine, Division of Infectious Disease (0676), University of California, San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0676. Fax: (858) 552-8585, ext. 2616. Fax: (858) 534-6133. E-mail: khostetler{at}ucsd.edu

Published ahead of print on 23 July 2007.

---

Antimicrobial Agents and Chemotherapy, October 2007, p. 3505-3509, Vol. 51, No. 10
0066-4804/07/$08.00+0     doi:10.1128/AAC.00460-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

This article has been cited by other articles:

• Morrey, J. D., Korba, B. E., Beadle, J. R., Wyles, D. L., Hostetler, K. Y. (2009). Alkoxyalkyl Esters of 9-(S)-(3-Hydroxy-2-Phosphonomethoxypropyl) Adenine Are Potent and Selective Inhibitors of Hepatitis B Virus (HBV) Replication In Vitro and in HBV Transgenic Mice In Vivo. Antimicrob. Agents Chemother. 53: 2865-2870 [Abstract] [Full Text]  
• Wyles, D. L., Kaihara, K. A., Korba, B. E., Schooley, R. T., Beadle, J. R., Hostetler, K. Y. (2009). The Octadecyloxyethyl Ester of (S)-9-[3-Hydroxy-2-(Phosphonomethoxy) Propyl]Adenine Is a Potent and Selective Inhibitor of Hepatitis C Virus Replication in Genotype 1A, 1B, and 2A Replicons. Antimicrob. Agents Chemother. 53: 2660-2662 [Abstract] [Full Text]