Abstract
Alkoxyalkyl esters of cidofovir, an acyclic nucleoside phosphonate, have been shown to have antiviral activities several orders of magnitude greater than unmodified cidofovir against cytomegalovirus, herpes simplex virus, vaccinia, cowpox, ectromelia and adenoviruses in vitro. Hexadecyloxypropyl-cidofovir is orally bioavailable and active in lethal animal models of vaccinia, cowpox, ectromelia and cytomegalovirus. To see if this strategy is also applicable to other acyclic nucleoside phosphonates, we have converted several phosophonomethoxyethyl purines and pyrimidines to their hexadecyloxypropyl, octadecyloxyethyl and oleyloxyethyl esters and compared their activity against HIV-1 with the activity of the respective unmodified acyclic nucleoside phosphonates. The hexadecyloxypropyl esters of phosphonomethoxyethyl-adenine, phosphonomethoxyethyl-2,6-diaminopurine and phosphonomethoxyethyl-N(6)-cyclopropyl-diaminopurine were 3-5 orders of magnitude more active against HIV-1 in vitro than the parent nucleotides. The EC(50) values for these compounds were in the 10-20 pM range with selective indexes of 1,250 to >4,000. The acyclic pyrimidine phosphonates were generally inactive against HIV-1 in vitro. Phosphonomethoxyethyl-cytosine ...Continue Reading
References
Dec 1, 1987·Antiviral Research·E De ClercqA Holý
Oct 2, 1986·Nature·E De ClercqP C Maudgal
Jun 23, 1999·Journal of Medicinal Chemistry·A HolýE De Clercq
Mar 19, 2002·Antimicrobial Agents and Chemotherapy·Earl R KernKarl Y Hostetler
Jul 18, 2002·Antimicrobial Agents and Chemotherapy·James R BeadleKarl Y Hostetler
Jan 27, 2004·Antimicrobial Agents and Chemotherapy·Debra C QuenelleEarl R Kern
Feb 20, 2004·Virology·R Mark BullerKarl Y Hostetler
May 6, 2004·Journal of Clinical Virology : the Official Publication of the Pan American Society for Clinical Virology·Erik De Clercq
Jul 10, 2004·The Journal of Infectious Diseases·Deborah J BidansetEarl R Kern
Aug 30, 2005·Antimicrobial Agents and Chemotherapy·Stephanie L Williams-AzizEarl R Kern
Nov 3, 2005·Nature Reviews. Drug Discovery·Erik De Clercq, Antonín Holý
Citations
Nov 30, 2006·Antimicrobial Agents and Chemotherapy·Hyunah ChooKarl Y Hostetler
Jul 25, 2007·Antimicrobial Agents and Chemotherapy·George R PainterKarl Y Hostetler
Oct 15, 2008·Antimicrobial Agents and Chemotherapy·Mark N PrichardKarl Y Hostetler
Mar 11, 2010·Chemotherapy·Nadejda ValiaevaKarl Y Hostetler
Sep 4, 2009·Future Virology·Scott ParkerR Mark Buller
Nov 26, 2010·Virus Research·Mark N Prichard, Earl R Kern
Aug 22, 2014·Chemical Reviews·Ugo PradereRaymond F Schinazi
Jul 31, 2013·Medicinal Research Reviews·Ondřej Baszczyňski, Zlatko Janeba
May 9, 2009·Antiviral Research·Karl Y Hostetler
Dec 23, 2014·The Journal of Organic Chemistry·Sarah J KeaneAnita R Maguire
Nov 9, 2017·Drug Delivery·Mei ChenLingyun Cheng
Mar 14, 2007·Archiv der Pharmazie·Samia M RidaMona H Badr
Apr 18, 2019·Beilstein Journal of Organic Chemistry·David J JonesTimothy P O'Sullivan
Apr 23, 2008·Current Protocols in Nucleic Acid Chemistry·James R Beadle
Nov 8, 2007·The Journal of Organic Chemistry·Alicia BotoEleuterio Alvarez
Sep 3, 2010·Journal of Medicinal Chemistry·Marcela KrecmerováRobert Snoeck
Dec 10, 2016·Journal of Medicinal Chemistry·James R BeadleKarl Y Hostetler