Filibuvir

Filibuvir

Systematic (IUPAC) name
(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
Clinical data
Routes of administration	Oral
Legal status
Legal status	Development terminated
Identifiers
CAS Number	877130-28-4
ATC code	none
PubChem	CID 54708673
ChemSpider	26286922
UNII	198J479Y2L
KEGG	D09616
ChEMBL	CHEMBL490672
Synonyms	PF-00868554
PDB ligand ID	AG0 (PDBe, RCSB PDB)
Chemical data
Formula	C29H37N5O3
Molar mass	503.636 g/mol
SMILES CCC1=CC(=CC(=N1)CC)CC[C@@]2(CC(=C(C(=O)O2)CC3=NN4C(=CC(=NC4=N3)C)C)O)C5CCCC5
InChI 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

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]

Its investigation was discontinued on 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, S. T.; Herlihy, K. J.; Graham, J. P.; Nonomiya, J.; Rahavendran, S. V.; Skor, H.; Irvine, R.; Binford, S.; Tatlock, J.; Li, H.; Gonzalez, J.; Linton, A.; Patick, A. K.; Lewis, C. (23 March 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.
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: the Investigational Drugs Journal 13 (12): 938–48. PMID 21154154.
5. "Pfizer Stops Developing Hepatitis C Drug". The Wall Street Journal. Dow Jones & Company, Inc. Retrieved 5 December 2015.
6. Gentile, Ivan; Buonomo, Antonio Riccardo; Zappulo, Emanuela; Borgia, Guglielmo (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.