Filibuvir

Filibuvir (also known as PF-00868554, PF-868554) was a non-nucleoside orally available[1] NS5B inhibitor developed by Pfizer for the treatment of hepatitis C. It binds to the non-catalytic Thumb II allosteric pocket of NS5B viral polymerase and causes a decrease in viral RNA synthesis. It is a potent and selective inhibitor, with a mean IC50 of 0.019 μM against genotype 1 polymerases.[2] Several filibuvir-resistant mutations have been identified, M423 being the most common that occurred after filibuvir monotherapy.[3] It was intended to be taken twice-daily.[4]

Filibuvir
Clinical data
Other namesPF-00868554
Routes of
administration		Oral
ATC code
  • none
Legal status
Legal status
  • Development terminated
Identifiers
  • (2R)-2-cyclopentyl-2-[2-(2,6-diethylpyridin-4-yl)ethyl]-5-[(5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl)methyl]-4-hydroxy-3H-pyran-6-one
CAS Number
PubChem CID
ChemSpider
UNII
KEGG
ChEMBL
PDB ligand
CompTox Dashboard (EPA)
Chemical and physical data
FormulaC29H37N5O3
Molar mass503.647 g·mol−1
3D model (JSmol)
  • CCC1=CC(=CC(=N1)CC)CC[C@@]2(CC(=C(C(=O)O2)CC3=NN4C(=CC(=NC4=N3)C)C)O)C5CCCC5
  • InChI=1S/C29H37N5O3/c1-5-22-14-20(15-23(6-2)31-22)11-12-29(21-9-7-8-10-21)17-25(35)24(27(36)37-29)16-26-32-28-30-18(3)13-19(4)34(28)33-26/h13-15,21,35H,5-12,16-17H2,1-4H3/t29-/m1/s1
  • Key:SLVAPEZTBDBAPI-GDLZYMKVSA-N

Its investigation was discontinued in February 2013 due to strategic reasons.[5][6]

References
  1. "Pfizer Halts Development of Hepatitis C Drug Filibuvir: Report". FirstWorld Pharma. Doctor's Guide Publishing Limited. Retrieved 5 December 2015.
  2. Shi ST, Herlihy KJ, Graham JP, Nonomiya J, Rahavendran SV, Skor H, et al. (June 2009). "Preclinical characterization of PF-00868554, a potent nonnucleoside inhibitor of the hepatitis C virus RNA-dependent RNA polymerase". Antimicrobial Agents and Chemotherapy. 53 (6): 2544–52. doi:10.1128/AAC.01599-08. PMC 2687230. PMID 19307358.
  3. Jiao P, Xue W, Shen Y, Jin N, Liu H (April 2014). "Understanding the drug resistance mechanism of hepatitis C virus NS5B to PF-00868554 due to mutations of the 423 site: a computational study". Molecular BioSystems. 10 (4): 767–77. doi:10.1039/c3mb70498j. PMID 24452008.
  4. Beaulieu PL (December 2010). "Filibuvir, a non-nucleoside NS5B polymerase inhibitor for the potential oral treatment of chronic HCV infection". IDrugs. 13 (12): 938–48. PMID 21154154.
  5. Loftus P (8 March 2013). "Pfizer Stops Developing Hepatitis C Drug". The Wall Street Journal. Dow Jones & Company, Inc. Retrieved 5 December 2015.
  6. Gentile I, Buonomo AR, Zappulo E, Borgia G (February 2015). "Discontinued drugs in 2012 - 2013: hepatitis C virus infection". Expert Opinion on Investigational Drugs. 24 (2): 239–51. doi:10.1517/13543784.2015.982274. PMID 25384989. S2CID 39936873.


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