title: Pradefovir: a prodrug that targets adefovir to the liver for the treatment of hepatitis B.
abstract: Adefovir dipivoxil, a marketed drug for the treatment of hepatitis B, is dosed at submaximally efficacious doses because of renal toxicity. In an effort to improve the therapeutic index of adefovir, 1-aryl-1,3-propanyl prodrugs were synthesized with the rationale that this selectively liver-activated prodrug class would enhance liver levels of the active metabolite adefovir diphosphate (ADV-DP) and/or decrease kidney exposure. The lead prodrug (14, MB06866, pradefovir), identified from a variety of in vitro and in vivo assays, exhibited good oral bioavailability (F = 42%, mesylate salt, rat) and rate of prodrug conversion to ADV-DP. Tissue distribution studies in the rat using radiolabeled materials showed that cyclic 1-aryl-1,3-propanyl prodrugs enhance the delivery of adefovir and its metabolites to the liver, with pradefovir exhibiting a 12-fold improvement in the liver/kidney ratio over adefovir dipivoxil.
authors.affiliation: Department of Chemistry and Biochemistry, Metabasis Therapeutics Inc, La Jolla, CA 92037, USA. rajar@mbasis.com
authors.forename: K Raja
authors.initials: KR
authors.lastname: Reddy
authors.forename: Michael C
authors.initials: MC
authors.lastname: Matelich
authors.forename: Bheemarao G
authors.initials: BG
authors.lastname: Ugarkar
authors.forename: Jorge E
authors.initials: JE
authors.lastname: Gómez-Galeno
authors.forename: Jay
authors.initials: J
authors.lastname: DaRe
authors.forename: Kristin
authors.initials: K
authors.lastname: Ollis
authors.forename: Zhili
authors.initials: Z
authors.lastname: Sun
authors.forename: William
authors.initials: W
authors.lastname: Craigo
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Colby
authors.forename: James M
authors.initials: JM
authors.lastname: Fujitaki
authors.forename: Serge H
authors.initials: SH
authors.lastname: Boyer
authors.forename: Paul D
authors.initials: PD
authors.lastname: van Poelje
authors.forename: Mark D
authors.initials: MD
authors.lastname: Erion
mesh_terms: D000225:Adenine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000493:pharmacokinetics; D000284:Administration, Oral; D000818:Animals; D001682:Biological Availability; D004285:Dogs; D022781:Hepatocytes / Q000378:metabolism; D066298:In Vitro Techniques; D008099:Liver / Q000378:metabolism*; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D063065:Organophosphonates / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D009943:Organophosphorus Compounds / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000493:pharmacokinetics; D011355:Prodrugs; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D063065:Organophosphonates; D009943:Organophosphorus Compounds; D011355:Prodrugs; C053001:adefovir; C497721:pradefovir; D000225:Adenine