title: Pronounced in vitro and in vivo antiretroviral activity of 5-substituted 2,4-diamino-6-[2-(phosphonomethoxy)ethoxy] pyrimidines.
abstract: OBJECTIVE
  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.
authors.affiliation: Rega Institute for Medical Research, K.U.Leuven, B-3000 Leuven, Belgium. jan.balzarini@rega.kuleuven.be
authors.forename: Jan
authors.initials: J
authors.lastname: Balzarini
authors.forename: Dominique
authors.initials: D
authors.lastname: Schols
authors.forename: Kristel
authors.initials: K
authors.lastname: Van Laethem
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.forename: Dana
authors.initials: D
authors.lastname: Hocková
authors.forename: Milina
authors.initials: M
authors.lastname: Masojidkova
authors.forename: Antonin
authors.initials: A
authors.lastname: Holý
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D002460:Cell Line; D024882:Drug Resistance, Viral; D015497:HIV-1 / Q000187:drug effects; D015498:HIV-2 / Q000187:drug effects; D006801:Humans; D051379:Mice; D008980:Moloney murine sarcoma virus; D063065:Organophosphonates / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology*; D012192:Retroviridae Infections / Q000188:drug therapy; D012513:Sarcoma, Experimental / Q000188:drug therapy; D013329:Structure-Activity Relationship; D000068698:Tenofovir; D014412:Tumor Virus Infections / Q000188:drug therapy
chemical_list: D019380:Anti-HIV Agents; D063065:Organophosphonates; D011743:Pyrimidines; C053001:adefovir; D000068698:Tenofovir; D000225:Adenine