title: Discovery of 1-((2R,4aR,6R,7R,7aR)-2-Isopropoxy-2-oxidodihydro-4H,6H-spiro[furo[3,2-d][1,3,2]dioxaphosphinine-7,2'-oxetan]-6-yl)pyrimidine-2,4(1H,3H)-dione (JNJ-54257099), a 3'-5'-Cyclic Phosphate Ester Prodrug of 2'-Deoxy-2'-Spirooxetane Uridine Triphosphate Useful for HCV Inhibition.
abstract: JNJ-54257099 (9) is a novel cyclic phosphate ester derivative that belongs to the class of 2'-deoxy-2'-spirooxetane uridine nucleotide prodrugs which are known as inhibitors of the HCV NS5B RNA-dependent RNA polymerase (RdRp). In the Huh-7 HCV genotype (GT) 1b replicon-containing cell line 9 is devoid of any anti-HCV activity, an observation attributable to inefficient prodrug metabolism which was found to be CYP3A4-dependent. In contrast, in vitro incubation of 9 in primary human hepatocytes as well as pharmacokinetic evaluation thereof in different preclinical species reveals the formation of substantial levels of 2'-deoxy-2'-spirooxetane uridine triphosphate (8), a potent inhibitor of the HCV NS5B polymerase. Overall, it was found that 9 displays a superior profile compared to its phosphoramidate prodrug analogues (e.g., 4) described previously. Of particular interest is the in vivo dose dependent reduction of HCV RNA observed in HCV infected (GT1a and GT3a) human hepatocyte chimeric mice after 7 days of oral administration of 9.
authors.affiliation: Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Tim H M
authors.initials: TH
authors.lastname: Jonckers
authors.affiliation: Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Abdellah
authors.initials: A
authors.lastname: Tahri
authors.affiliation: Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Leen
authors.initials: L
authors.lastname: Vijgen
authors.affiliation: Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Jan Martin
authors.initials: JM
authors.lastname: Berke
authors.affiliation: Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Sophie
authors.initials: S
authors.lastname: Lachau-Durand
authors.affiliation: Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Bart
authors.initials: B
authors.lastname: Stoops
authors.affiliation: Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Jan
authors.initials: J
authors.lastname: Snoeys
authors.affiliation: Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Laurent
authors.initials: L
authors.lastname: Leclercq
authors.affiliation: Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Lotke
authors.initials: L
authors.lastname: Tambuyzer
authors.affiliation: Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Tse-I
authors.initials: TI
authors.lastname: Lin
authors.affiliation: Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Kenny
authors.initials: K
authors.lastname: Simmen
authors.affiliation: Janssen Infectious Diseases - Diagnostics BVBA , Turnhoutseweg 30, 2340 Beerse, Belgium.
authors.forename: Pierre
authors.initials: P
authors.lastname: Raboisson
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D055808:Drug Discovery; D015658:HIV Infections / Q000188:drug therapy* / Q000821:virology; D016174:Hepacivirus / Q000187:drug effects*; D022781:Hepatocytes / Q000187:drug effects* / Q000821:virology; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D011355:Prodrugs / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D011744:Pyrimidinones / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013141:Spiro Compounds / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors; D014779:Virus Replication / Q000187:drug effects; D012324:RNA-Dependent RNA Polymerase
chemical_list: D000998:Antiviral Agents; D011355:Prodrugs; D011744:Pyrimidinones; D013141:Spiro Compounds; D017361:Viral Nonstructural Proteins; C000620011:1-2-isopropoxy-2-oxidodihydro-4H,6H-spiro(furo(3,2-d)(1,3,2)dioxaphosphinine-7,2'-oxetan)-6-yl)pyrimidine-2,4(1H,3H)-dione; C087036:NS-5 protein, hepatitis C virus; D012324:RNA-Dependent RNA Polymerase