Pronounced in vitro and in vivo antiretroviral activity of 5-substituted 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy] pyrimidines.


OBJECTIVES To discover new potent and selective anti-human immunodeficiency virus (HIV) acyclic nucleoside phosphonate (ANP) drugs with in vivo antiretroviral activity. METHODS New acyclic pyrimidine nucleoside phosphonate derivatives that mimic the structure of the anti-HIV purine nucleoside phosphonates 9-(2-phosphonylmethoxyethyl)adenine (PMEA, adefovir) and (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA, tenofovir) were designed by linking the acyclic side chain of the ANPs through an ether bond to the C-6 position instead of the N-1 position of the pyrimidine ring. The compounds were evaluated against HIV and Moloney murine sarcoma virus (MSV) in cell culture, including a broad variety of HIV-1 clade clinical isolates and relevant mutant (drug-resistant) HIV-1 isolates. Their antiviral activities were correlated and investigated in an in vivo model consisting of MSV-infected newborn mice. MSV-induced tumour formation and associated death were recorded in drug-treated animals. RESULTS Several 5-substituted 6-[2-(phosphonomethoxy)ethoxy]-2,4-diaminopyrimidine (PMEO-DAPy) analogues were found to inhibit a broad variety of HIV-1 clinical isolates. They showed a more favourable cross-resistance profile to mutant virus isolates than adefovir and tenofovir. There was a close correlation between inhibition of MSV in C3H/3T3 cells and inhibition of HIV-1 in CEM cells. The PMEO-DAPy derivatives potently inhibited MSV-induced tumour cell formation in newborn mice. The 5-methyl analogue PMEO-5-Me-DAPy proved markedly more inhibitory to MSV-induced tumour cell formation and associated animal death than its unsubstituted parent PMEO-DAPy derivative. When compared with adefovir, PMEO-5-Me-DAPy was less toxic and more antivirally active in MSV-infected mice. CONCLUSIONS PMEO-5-Me-DAPy deserves further (pre)clinical investigations as a candidate anti-HIV drug.

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@article{Balzarini2007PronouncedIV, title={Pronounced in vitro and in vivo antiretroviral activity of 5-substituted 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy] pyrimidines.}, author={Jan Balzarini and Dominique Schols and Kristel van Laethem and Erik de Clercq and Dana Hockov{\'a} and Milina Masojidkova and Anton{\'i}n Hol{\'y}}, journal={The Journal of antimicrobial chemotherapy}, year={2007}, volume={59 1}, pages={80-6} }