Design, synthesis and evaluation of a novel double pro-drug: INX-08189. A new clinical candidate for hepatitis C virus.

Bioorganic & Medicinal Chemistry Letters
Christopher McGuiganGeoffrey Henson

Abstract

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.

References

Dec 9, 2000·Science·K J BlightC M Rice
Mar 7, 2008·Expert Opinion on Emerging Drugs·Vincent SorianoPablo Barreiro

❮ Previous
Next ❯

Citations

Nov 2, 2011·Journal of Medicinal Chemistry·Christopher McGuiganStanley Chamberlain
Dec 22, 2011·Journal of Medicinal Chemistry·Michael J SofiaBruce S Ross
Sep 16, 2011·The Journal of Organic Chemistry·Bruce S RossMichael J Sofia
Feb 10, 2011·ACS Medicinal Chemistry Letters·Wonsuk ChangMichael J Sofia
Mar 31, 2012·Future Medicinal Chemistry·Karolina Madela, Christopher McGuigan
Nov 28, 2013·Antiviral Research·Steven J CoatsRaymond F Schinazi
Aug 28, 2013·Archives of Virology·Muhammad ImranMuhammad Ashraf
Sep 29, 2011·Annual Review of Medicine·Dahlene N Fusco, Raymond T Chung
May 23, 2014·Expert Opinion on Investigational Drugs·Ivan GentileGuglielmo Borgia
Sep 1, 2011·Antiviral Research·Adrian S Ray, Karl Y Hostetler
Sep 24, 2015·Nucleosides, Nucleotides & Nucleic Acids·Thorsten A KirschbergChoung U Kim
Sep 1, 2012·Reviews in Medical Virology·Erik De Clercq
May 4, 2012·Medicinal Research Reviews·Erik De Clercq
Nov 18, 2015·Journal of Natural Products·Christina NordAnders Broberg
Nov 2, 2013·European Journal of Medicinal Chemistry·Christopher McGuiganJan Balzarini
Jul 26, 2015·Journal of Chromatography. B, Analytical Technologies in the Biomedical and Life Sciences·Ang LiuJian Wang
Apr 1, 2015·Future Medicinal Chemistry·Valentina Ferrari, Michaela Serpi
Oct 1, 2013·Antiviral Research·Siew Pheng LimPei-Yong Shi
May 3, 2014·Organic Letters·Roger A Ashmus, Todd L Lowary
Jun 28, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Anders BrobergJolanta J Levenfors
Oct 17, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Hanadi SinokrotRafik Karaman
Feb 22, 2018·Antiviral Chemistry & Chemotherapy·Cyril B Dousson
Aug 24, 2011·Antiviral Chemistry & Chemotherapy·Michael J Sofia
Nov 29, 2013·Journal of Labelled Compounds & Radiopharmaceuticals·John A EasterSamuel J Bonacorsi
Jun 19, 2013·Current Protocols in Nucleic Acid Chemistry·Michaela SerpiMagdalena Slusarczyk
May 23, 2020·Cancer Chemotherapy and Pharmacology·Mansi AroraMitesh J Borad
May 25, 2018·Antiviral Chemistry & Chemotherapy·Magdalena SlusarczykFabrizio Pertusati
May 10, 2016·ChemMedChem·Youcef Mehellou
Feb 23, 2020·Virus Genes·J J BugertA Brancale
Aug 22, 2020·ACS Pharmacology & Translational Science·Andrew J Wiemer
May 15, 2021·Expert Opinion on Drug Discovery·Michaela Serpi, Fabrizio Pertusati
Oct 31, 2017·Journal of Natural Products·Joakim BjerketorpAnders Broberg
Oct 15, 2019·The Journal of Organic Chemistry·Hyejin LeeLak Shin Jeong

❮ Previous
Next ❯

Related Concepts

Related Feeds

Antivirals

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.

Antivirals (ASM)

Antivirals are medications that are used specifically for treating viral infections. Discover the latest research on antivirals here.