title: A prodrug strategy for the oral delivery of a poorly soluble HCV NS5B thumb pocket 1 polymerase inhibitor using self-emulsifying drug delivery systems (SEDDS).
abstract: A prodrug approach was developed to address the low oral bioavailability of a poorly soluble (<0.1μg/mL in pH 6.8 buffer) but highly permeable thumb pocket 1 HCV NS5B polymerase inhibitor. Bioconversion rates of structurally diverse prodrug derivatives were evaluated in a panel of in vitro assays using microsomes, from either liver or intestinal tissues, simulated intestinal fluids, simulated gastric fluids or plasma. In vivo bioconversion of promising candidates was evaluated following oral administration to rats. The most successful strategy involved modification of the parent drug carboxylic acid moiety to glycolic amide esters which improved solubility in lipid-based self-emulsifying drug delivery systems (SEDDS). Crystalline prodrug analog 36 (mp 161°C) showed good solubility in individual SEDDS components (up to 80mg/mL) compared to parent 2 (<3mg/mL; mp 267°C) and cross-species bioconversions which correlated with in vitro stability in liver microsomes.
authors.affiliation: Medicinal Chemistry Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada. Electronic address: resgeneral.lav@boehringer-ingelheim.com.
authors.forename: Pierre L
authors.initials: PL
authors.lastname: Beaulieu
authors.affiliation: Biology Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
authors.forename: Josie
authors.initials: J
authors.lastname: De Marte
authors.affiliation: Biology Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
authors.forename: Michel
authors.initials: M
authors.lastname: Garneau
authors.affiliation: Biology Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
authors.forename: Laibin
authors.initials: L
authors.lastname: Luo
authors.affiliation: Medicinal Chemistry Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
authors.forename: Timothy
authors.initials: T
authors.lastname: Stammers
authors.affiliation: Boehringer Ingelhein Pharmaceuticals Inc., 175 Briar Ridge Road, Ridgefield, CT 06877, United States.
authors.forename: Chitra
authors.initials: C
authors.lastname: Telang
authors.affiliation: Medicinal Chemistry Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
authors.forename: Dominik
authors.initials: D
authors.lastname: Wernic
authors.affiliation: Biology Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
authors.forename: George
authors.initials: G
authors.lastname: Kukolj
authors.affiliation: Biology Department, Boehringer Ingelheim (Canada) Ltd, Research and Development, 2100 Cunard Street, Laval, Quebec H7S 2G5, Canada.
authors.forename: Jianmin
authors.initials: J
authors.lastname: Duan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D016503:Drug Delivery Systems / Q000379:methods*; D004655:Emulsions / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D008861:Microsomes / Q000187:drug effects / Q000378:metabolism; D019384:Nucleic Acid Synthesis Inhibitors / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D011355:Prodrugs / Q000008:administration & dosage* / Q000737:chemistry / Q000378:metabolism; D051381:Rats; D012995:Solubility; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D012324:RNA-Dependent RNA Polymerase
chemical_list: D004655:Emulsions; D019384:Nucleic Acid Synthesis Inhibitors; D011355:Prodrugs; D017361:Viral Nonstructural Proteins; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase
keywords: Antiviral; Hepatitis C virus; Inhibitor; NS5B polymerase; Prodrug