Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus.
We herein report a novel double pro-drug approach applied to the anti-HCV agent 2'-beta-C-methyl guanosine. A phosphoramidate ProTide motif and a 6-O-methoxy base pro-drug moiety are combined to generate lipophilic prodrugs of the monophosphate of the guanine nucleoside. Modification of the ester and amino acid moieties lead to a compound INX-08189 that exhibits 10nM potency in the HCV genotype 1b subgenomic replicon, thus being 500 times more potent than the parent nucleoside. The potency of the lead compound INX-08189 was shown to be consistent with intracellular 2'-C-methyl guanosine triphosphate levels in primary human hepatocytes. The separated diastereomers of INX-08189 were shown to have similar activity in the replicon assay and were also shown to be similar substrates for enzyme processing. INX-08189 has completed investigational new drug enabling studies and has been progressed into human clinical trials for the treatment of chronic HCV infection.
McGuigan
Christopher
C
Welsh School of Pharmacy, Cardiff University, King Edward VII Avenue, Cardiff CF10 3NB, UK. mcguigan@cf.ac.uk
Madela
Karolina
K
Aljarah
Mohamed
M
Gilles
Arnaud
A
Brancale
Andrea
A
Zonta
Nicola
N
Chamberlain
Stanley
S
Vernachio
John
J
Hutchins
Jeff
J
Hall
Andrea
A
Ames
Brenda
B
Gorovits
Elena
E
Ganguly
Babita
B
Kolykhalov
Alexander
A
Wang
Jin
J
Muhammad
Jerry
J
Patti
Joseph M
JM
Henson
Geoffrey
G
D000577:Amides / Q000737:chemistry; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity; D002478:Cells, Cultured; D015195:Drug Design; D006151:Guanosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000633:toxicity; D006157:Guanosine Monophosphate / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D010756:Phosphoric Acids / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000633:toxicity
D000577:Amides; D000998:Antiviral Agents; D010756:Phosphoric Acids; D011355:Prodrugs; D006151:Guanosine; C553340:BMS-986094; D006157:Guanosine Monophosphate; C011067:phosphoramidic acid