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Acyclic Nucleoside Phosphonates
The leading line in our design of potential antimetabolites is their biological stability. This concept makes use of our previous study of the structure requirements of enzymes of nucleic acids metabolism and, in particular, our preceding systematic studies on acyclic nucleoside analogues. The sugar moiety in the nucleoside molecule is replaced by an acyclic chain and phosphoric acid ester by phosphonomethyl ether linkage. In the past fifteen years, we have discovered several bioactive derivatives and turned thus the attention to novel structural groups of acyclic nucleotide analogues possess high anti-DNAviral and antiretroviral activity. These studies culminated by the clinical development of three novel antivirals: In 1996, cidofovir (HMPC, Vistide™) was approved by FDA and EMEA for CMV retinitis in AIDS patients, oral prodrug of adefovir (PMEA), adefovir dipivoxil (Hepsera™) was approved for treatment of hepatitis B in 2002. Part of these studies connected with anti-AIDS drug development was honoured with the Descartes Prize of the European Union.
The structural design and synthesis in this field focused on the alteration of the heterocyclic base and of the side chain bearing the ether-bound phosphonate residue. The main effort concentrated on purine 9-[2-(phosphonomethoxy)propyl] derivatives (PMP-derivatives) - which show very strong antiretroviral activity and low toxicity. Oral prodrug of (R)-PMPA (tenofovir disoproxil) was approved in 2001 as an efficient drug for AIDS therapy (Viread™).
Contact:
RNDr.A.Holý, DrSc.
Institute of Organic Chemistry and Biochemistry
Flemingovo nám.2
CZ-166 10 Praha 6 Dejvice
Phone: +420-220183-384, +420-220183-262
Fax: +420-220183-560
E-mail: holy@uochb.cas.cz
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