Synthesis, Oral Bioavailability Determination, and in vitro Evaluation of Prodrugs of the Antiviral Agent 9-[2-(Phosphonomethoxy)ethyl]adenine (PMEA)

A series of phosphonate prodrugs were evaluated in an attempt to increase the oral bioavailability of the anti-HIV agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; 1). The majority of the bis(alkyl ester) and bis(alkyl amide) prodrugs were prepared by alcohol or amine displacement of dichlorophosph...

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Bibliographic Details
Published in:Journal of medicinal chemistry 1994-06, Vol.37 (12), p.1857-1864
Main Authors: Starrett, John E. Jr, Tortolani, David R, Russell, John, Hitchcock, Michael J. M, Whiterock, Valerie, Martin, John C, Mansuri, Muzammil M
Format: Article
Language:English
Subjects:
Adenine - analogs & derivatives
Adenine - chemical synthesis
Adenine - pharmacokinetics
Adenine - pharmacology
Animals
Antiviral Agents - chemical synthesis
Antiviral Agents - pharmacokinetics
Antiviral Agents - pharmacology
Biological Availability
Carbohydrates. Nucleosides and nucleotides
Chemistry
Exact sciences and technology
human immunodeficiency virus
Male
Nucleosides, nucleotides and oligonucleotides
Organic chemistry
Organophosphonates
Preparations and properties
Prodrugs - chemical synthesis
Prodrugs - pharmacokinetics
Prodrugs - pharmacology
Rats
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Summary:A series of phosphonate prodrugs were evaluated in an attempt to increase the oral bioavailability of the anti-HIV agent 9-[2-(phosphonomethoxy)ethyl]adenine (PMEA; 1). The majority of the bis(alkyl ester) and bis(alkyl amide) prodrugs were prepared by alcohol or amine displacement of dichlorophosphonate 2. Basic hydrolysis of the bis(esters) or bis(amides) provided the corresponding monoesters or monoamides. Synthesis of bis[(acyloxy)alkyl] phosphonates 10a-c was accomplished by alkylation of PMEA with the appropriate chloromethyl ether in the presence of N,N'-dicyclohexylmorpholinecarboxamidine. The systemic levels of PMEA following oral administration of a PMEA prodrug to rats were determined by measuring the concentration of PMEA in the urine for 48 h after administration of the prodrug. The oral bioavailability of PMEA employing this method was determined to be 7.8%. Oral dosing with bis(alkyl) phosphonates 3a,b resulted in apparent absorption of the prodrugs (> or = 40%), although neither of the esters were completely cleaved to liberate the parent phosphonate PMEA. The mono(alkyl esters) 7a-e and 8a,b exhibited poor oral bioavailability (< or = 5%). Phosphonamides 5, 6, and 9 were unstable under acidic conditions and provided levels of PMEA comparable to the parent compound after oral administration. Bis[(acyloxy)alkyl] phosphonates 10a-c demonstrated significantly improved oral bioavailabilities of 17.6%, 14.6%, and 15.4%, respectively. When evaluated in vitro against HSV-2, (acyloxy)alkyl phosphonates 10a-c were greater than 200-fold more active than PMEA.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm00038a015