Document Detail


Evolution of an amino acid based prodrug approach: stay tuned.
MedLine Citation:
PMID:  23339402     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Certain acyclic nucleoside phosphonates (ANPs) such as (S)-HPMPC (cidofovir, Vistide) and (S)-HPMPA have been shown to be active against a broad spectrum of DNA and retroviruses. However, their poor absorption as well as their toxicity limit the utilization of these therapeutics in the clinic. Nucleoside phosphonates are poorly absorbed primarily due to the presence of the phosphonic acid group, which ionizes at physiological pH. When dosed intravenously they display dose-limiting nephrotoxicity due to their accumulation in the kidney. To overcome these limitations, nucleoside phosphonate prodrug strategies have taken center stage in the development pathway and a number of different approaches are at various stages of development. Our efforts have focused on the development of ANP prodrugs in which a benign amino acid promoiety masks a phosphonate P-OH via a hydroxyl side chain. The design of these prodrugs incorporates multiple chemical groups (the P-X-C linkage, the amino acid stereochemistry, the C-terminal and N-terminal functional groups) that can be tuned to modify absorption, pharmacokinetic and efficacy properties with the goal of improving overall prodrug performance.
Authors:
Ivan S Krylov; Boris A Kashemirov; John M Hilfinger; Charles E McKenna
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural     Date:  2013-01-22
Journal Detail:
Title:  Molecular pharmaceutics     Volume:  10     ISSN:  1543-8392     ISO Abbreviation:  Mol. Pharm.     Publication Date:  2013 Feb 
Date Detail:
Created Date:  2013-02-04     Completed Date:  2013-08-20     Revised Date:  2014-02-05    
Medline Journal Info:
Nlm Unique ID:  101197791     Medline TA:  Mol Pharm     Country:  United States    
Other Details:
Languages:  eng     Pagination:  445-58     Citation Subset:  IM    
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MeSH Terms
Descriptor/Qualifier:
Amino Acids / chemistry*
Antiviral Agents / chemistry*
Cytosine / analogs & derivatives*,  chemistry
Molecular Structure
Organophosphonates / chemistry*
Prodrugs / chemistry*
Grant Support
ID/Acronym/Agency:
AI056864/AI/NIAID NIH HHS; AI061457/AI/NIAID NIH HHS; R43 AI056864/AI/NIAID NIH HHS; R43 AI100401/AI/NIAID NIH HHS; R44 AI056864/AI/NIAID NIH HHS; U01 AI061457/AI/NIAID NIH HHS
Chemical
Reg. No./Substance:
0/Amino Acids; 0/Antiviral Agents; 0/Organophosphonates; 0/Prodrugs; 8J337D1HZY/Cytosine; JIL713Q00N/cidofovir
Comments/Corrections

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