Metabolically stable alkoxyalkyl esters of antiviral or antiproliferative phosphonates, nucleoside phosphonates and nucleoside phosphates
Inventors
Hostetler, Karl Y. • Beadle, James R. • Ruiz, Jacqueline • Almond, Merrick R. • Painter, George R. • Riley, Timothy A. • Francom, Paula
Assignees
Chimerix Inc • US Department of Veterans Affairs • University of California San Diego UCSD
Publication Number
US-7749983-B2
Publication Date
2010-07-06
Expiration Date
2027-04-18
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Abstract
The present invention relates to phosphonate, nucleoside phosphonate or nucleoside phosphate compounds, compositions containing them, processes for obtaining them, and their use in treating a variety of medical disorders, in particular viral infections, cancers and the like.
Core Innovation
The invention relates to metabolically stable alkoxyalkyl esters of phosphonates, nucleoside phosphonates, and nucleoside phosphates, compositions containing them, methods for synthesizing them, and their use in treating viral infections, cancers, and similar medical disorders. These compounds are designed for oral administration to improve bioavailability and therapeutic effectiveness.
The problem addressed by the invention is that existing alkoxyalkyl esters such as hexadecyloxypropyl cidofovir (HDP-CDV) suffer from rapid metabolic inactivation via omega and beta oxidation in the liver and small intestine. This metabolism leads to degradation to inactive metabolites, which lowers plasma levels of the drug and reduces antiviral efficacy after oral administration.
The invention overcomes these drawbacks by introducing terminal or penultimate branched-chain, unsaturated, and halogen-substituted alkoxyalkyl esters of phosphonate compounds. These substituents provide metabolic stability by blocking or slowing omega oxidation during absorption and first-pass metabolism, improving resistance to metabolic degradation, and thereby enhancing oral bioavailability and pharmacologic activity.
Claims Coverage
The patent includes multiple independent claims covering nucleoside phosphonate compounds with improved metabolic stability, their structural features, and their therapeutic use.
Nucleoside phosphonates with branched, unsaturated, or halogen-substituted alkoxyalkyl esters
Compounds comprising nucleoside phosphonates substituted with alkoxyalkyl groups having terminal or penultimate branched alkyl groups, double bonds, or halogen atoms, which confer metabolic stability by preventing or decreasing metabolic degradation of the phosphonate.
Specific structural formulas for resistance to metabolism
Nucleoside phosphonates wherein R groups are specifically selected from defined branched methylalkoxyalkyl, fluoroalkoxyalkyl, or other substituted alkoxyalkyl moieties at or near the terminal positions of the alkyl chain to block omega oxidation.
Inclusion of broad families of antiviral and antineoplastic nucleoside phosphonates
Phosphonate compounds including those derived from cidofovir, cyclic cidofovir, HPMPA, and their alkoxyalkyl esters bearing the described substituents, which have antiviral or anticancer activities.
Pharmaceutical compositions containing the metabolically stable esters
Formulations comprising the nucleoside phosphonates with branched, unsaturated, or halogen-substituted alkoxyalkyl esters along with pharmaceutically acceptable carriers suitable for treatment via administration routes including oral delivery.
Methods of treating viral infections by administering the phosphonate compounds
Therapeutic methods comprising administering an effective amount of the metabolically stable alkoxyalkyl ester phosphonate compounds to a host to treat viral infections.
The independent claims cover nucleoside phosphonate compounds structurally defined by branched, unsaturated, or halogen-substituted alkoxyalkyl ester groups that confer metabolic stability, pharmaceutical compositions containing them, and methods for treating viral infections using these compounds, thus addressing the problem of rapid metabolic degradation limiting oral efficacy.
Stated Advantages
The compounds have increased metabolic stability against omega and beta oxidation during absorption and first-pass metabolism.
The increased metabolic stability improves oral bioavailability of antiviral and antiproliferative phosphonate drugs.
The prodrugs show enhanced antiviral efficacy and potency in vitro and in vivo at submicromolar concentrations.
The branched or substituted alkoxyalkyl ester derivatives exhibit slower degradation by liver enzymes compared to straight-chain analogs.
Documented Applications
Treatment of viral infections including human immunodeficiency virus (HIV), influenza, herpes simplex virus, human herpesviruses 6 and 8, cytomegalovirus, hepatitis B and C virus, Epstein-Barr virus, varicella zoster virus, orthopox viruses such as smallpox and monkeypox, Ebola virus, papilloma virus, and related diseases.
Treatment of cancers and disorders caused by inappropriate cell proliferation such as melanoma, lung cancer, pancreatic, stomach, colon and rectal cancers, prostate, breast cancer, leukemias, and lymphomas.
Use as oral antiviral and anticancer agents via various administration routes including oral, parenteral, topical, transdermal, rectal, and inhalation.
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