title: Serine peptide phosphoester prodrugs of cyclic cidofovir: synthesis, transport, and antiviral activity.
abstract: Cidofovir (HPMPC, 1), a broad-spectrum antiviral agent, is currently used to treat AIDS-related human cytomegalovirus (HCMV) retinitis and has recognized therapeutic potential for orthopox virus infections, but is limited by its low oral bioavailability. Cyclic cidofovir (2) displays decreased nephrotoxicity compared to 1, while also exhibiting potent antiviral activity. Here we describe in detail the synthesis and evaluation as prodrugs of four cHPMPC dipeptide conjugates in which the free POH of 2 is esterified by the Ser side chain alcohol group of an X-L-Ser(OMe) dipeptide: 3 (X=L-Ala), 4 (X=L-Val), 5 (X=L-Leu), and 6 (X=L-Phe). Perfusion studies in the rat establish that the mesenteric permeability to 4 is more than 20-fold greater than to 1, and the bioavailability of 4 is increased 6-fold relative to 1 in an in vivo murine model. In gastrointestinal and liver homogenates, the cHPMPC prodrugs are rapidly hydrolyzed to 2. Prodrugs 3, 4, and 5 are nontoxic at 100 microM in HFF and KB cells and in cell-based plaque reduction assays had IC 50 values of 0.1-0.5 microM for HCMV and 10 microM for two orthopox viruses (vaccinia and cowpox). The enhanced transport properties of 3-6, conferred by incorporation of a biologically benign dipeptide moiety, and the facile cleavage of the Ser-O-P linkage suggest that these prodrugs represent a promising new approach to enhancing the bioavailability of 2.
authors.affiliation: Department of Chemistry, University of Southern California, Los Angeles, California 90089-0744, USA.
authors.forename: Ulrika
authors.initials: U
authors.lastname: Eriksson
authors.forename: Larryn W
authors.initials: LW
authors.lastname: Peterson
authors.forename: Boris A
authors.initials: BA
authors.lastname: Kashemirov
authors.forename: John M
authors.initials: JM
authors.lastname: Hilfinger
authors.forename: John C
authors.initials: JC
authors.lastname: Drach
authors.forename: Katherine Z
authors.initials: KZ
authors.lastname: Borysko
authors.forename: Julie M
authors.initials: JM
authors.lastname: Breitenbach
authors.forename: Jae Seung
authors.initials: JS
authors.lastname: Kim
authors.forename: Stefanie
authors.initials: S
authors.lastname: Mitchell
authors.forename: Paul
authors.initials: P
authors.lastname: Kijek
authors.forename: Charles E
authors.initials: CE
authors.lastname: McKenna
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D000077404:Cidofovir; D003587:Cytomegalovirus / Q000187:drug effects; D003596:Cytosine / Q000031:analogs & derivatives* / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D004951:Esterification; D006801:Humans; D006868:Hydrolysis; D007413:Intestinal Mucosa / Q000378:metabolism; D008297:Male; D051379:Mice; D008958:Models, Molecular; D015394:Molecular Structure; D063065:Organophosphonates / Q000097:blood / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry*; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D012694:Serine / Q000737:chemistry; D055672:Static Electricity
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D010455:Peptides; D011355:Prodrugs; D012694:Serine; D003596:Cytosine; D000077404:Cidofovir