title: Design, synthesis, and characterization of a series of cytochrome P(450) 3A-activated prodrugs (HepDirect prodrugs) useful for targeting phosph(on)ate-based drugs to the liver.
abstract: A new class of phosphate and phosphonate prodrugs, called HepDirect prodrugs, is described that combines properties of rapid liver cleavage with high plasma and tissue stability to achieve increased drug levels in the liver. The prodrugs are substituted cyclic 1,3-propanyl esters designed to undergo an oxidative cleavage reaction catalyzed by a cytochrome P(450) (CYP) expressed predominantly in the liver. Reported herein is the discovery of a prodrug series containing an aryl substituent at C4 and its use for the delivery of nucleoside-based drugs to the liver. Prodrugs of 5'-monophosphates of vidarabine, lamivudine (3TC), and cytarabine as well as the phosphonic acid adefovir were shown to cleave following exposure to liver homogenates and exhibit good stability in blood and other tissues. Prodrug cleavage required the presence of the aryl group in the cis-configuration, but was relatively independent of the nucleoside and absolute stereochemistry at C4. Mechanistic studies suggested that prodrug cleavage proceeded via an initial CYP3A-catalyzed oxidation to an intermediate ring-opened monoacid, which subsequently was converted to the phosph(on)ate and an aryl vinyl ketone by a beta-elimination reaction. Studies in primary rat hepatocytes and normal rats comparing 3TC and the corresponding HepDirect prodrug demonstrated the ability of these prodrugs to effectively bypass the rate-limiting nucleoside kinase step and produce higher levels of the biologically active nucleoside triphosphate.
authors.affiliation: Departments of Medicinal Chemistry and Biochemistry, Metabasis Therapeutics, Inc., San Diego, California 92121 USA.
authors.forename: Mark D
authors.initials: MD
authors.lastname: Erion
authors.forename: K Raja
authors.initials: KR
authors.lastname: Reddy
authors.forename: Serge H
authors.initials: SH
authors.lastname: Boyer
authors.forename: Michael C
authors.initials: MC
authors.lastname: Matelich
authors.forename: Jorge
authors.initials: J
authors.lastname: Gomez-Galeno
authors.forename: Robert H
authors.initials: RH
authors.lastname: Lemus
authors.forename: Bheemarao G
authors.initials: BG
authors.lastname: Ugarkar
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Colby
authors.forename: Jürgen
authors.initials: J
authors.lastname: Schanzer
authors.forename: Paul D
authors.initials: PD
authors.lastname: Van Poelje
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism; D000818:Animals; D002384:Catalysis; D003561:Cytarabine / Q000378:metabolism; D003577:Cytochrome P-450 Enzyme System / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D016503:Drug Delivery Systems; D015195:Drug Design; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D063065:Organophosphonates / Q000737:chemistry / Q000378:metabolism; D010710:Phosphates / Q000737:chemistry / Q000378:metabolism; D010770:Phosphotransferases / Q000378:metabolism; D011355:Prodrugs / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism; D013997:Time Factors; D014740:Vidarabine / Q000378:metabolism
chemical_list: D063065:Organophosphonates; D010710:Phosphates; D011355:Prodrugs; D003561:Cytarabine; C053001:adefovir; D003577:Cytochrome P-450 Enzyme System; D010770:Phosphotransferases; C021892:nucleoside phosphotransferase; D014740:Vidarabine; D000225:Adenine