SOFOSBUVIR

Details

Stereochemistry	ABSOLUTE
Molecular Formula	C22H29FN3O9P
Molecular Weight	529.4525
Optical Activity	UNSPECIFIED
Defined Stereocenters	6 / 6
E/Z Centers	0
Charge	0

SHOW SMILES / InChI

SMILES

CC(C)OC(=O)[C@H](C)N[P@](=O)(OC[C@H]1O[C@@H](N2C=CC(=O)NC2=O)[C@](C)(F)[C@@H]1O)OC3=CC=CC=C3

InChI

InChIKey=TTZHDVOVKQGIBA-IQWMDFIBSA-N

InChI=1S/C22H29FN3O9P/c1-13(2)33-19(29)14(3)25-36(31,35-15-8-6-5-7-9-15)32-12-16-18(28)22(4,23)20(34-16)26-11-10-17(27)24-21(26)30/h5-11,13-14,16,18,20,28H,12H2,1-4H3,(H,25,31)(H,24,27,30)/t14-,16+,18+,20+,22+,36-/m0/s1

HIDE SMILES / InChI

Molecular Formula	C22H29FN3O9P
Molecular Weight	529.4525
Charge	0
Count	MOL RATIO 1 MOL RATIO (average)

Stereochemistry	ABSOLUTE
Additional Stereochemistry	No
Defined Stereocenters	6 / 6
E/Z Centers	0
Optical Activity	UNSPECIFIED

Description

Sofosbuvir is a nucleotide analog inhibitor of hepatitis C virus NS5B polymerase - the key enzyme mediating HCV RNA replication. Sofosbuvir is a prodrug and after ingestion it is rapidly converted to GS-331007, the predominant circulating drug that accounts for greater than 90% of the systemically active drug. The compound GS-331007 is efficiently taken up by hepatocytes, whereby cellular kinases convert GS-331007 to its pharmacologically active uridine analog 5’-triphosphate form (GS-461203). This triphosphate compound mimics the natural cellular uridine nucleotide and is incorporated by the HCV RNA polymerase into the elongating RNA primer strand, resulting in chain termination. The active form GS-461203 targets the NS5B catalytic site and acts as a non-obligate chain terminator. The active compound (GS-461203) does not inhibit host DNA polymerases, RNA polymerases, or mitochondrial RNA polymerase. Sofosbuvir (alone or in in combination with other medications) is used to treat Hepatitis C.

CNS Activity

Originator

Approval Year

Conditions

Conditions

Condition	Modality	Targets	Highest Phase	Product
Chronic hepatitis C 42	Primary		Approved 8,429	SOVALDI

C_max

Value	Dose	Co-administered	Analyte	Population
922.3 ng/mL	400 mg 1 times / day multiple, oral		SOFOSBUVIR plasma	Homo sapiens
1001.7 ng/mL	400 mg single, oral		SOFOSBUVIR plasma	Homo sapiens

AUC

Value	Dose	Co-administered	Analyte	Population
872.2 ng × h/mL	400 mg 1 times / day multiple, oral		SOFOSBUVIR plasma	Homo sapiens
969 ng × h/mL	400 mg 1 times / day steady-state, oral	Ribavirin	SOFOSBUVIR plasma	Homo sapiens
861 ng × h/mL	400 mg single, oral		SOFOSBUVIR plasma	Homo sapiens

T_1/2

Value	Dose	Co-administered	Analyte	Population
0.35 h	400 mg 1 times / day multiple, oral		SOFOSBUVIR plasma	Homo sapiens
0.4 h	400 mg 1 times / day steady-state, oral	Ribavirin	SOFOSBUVIR plasma	Homo sapiens
0.38 h	400 mg single, oral		SOFOSBUVIR plasma	Homo sapiens

F_unbound

Value	Dose	Co-administered	Analyte	Population
63%	400 mg 1 times / day steady-state, oral	Ribavirin	SOFOSBUVIR plasma	Homo sapiens

Doses

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Dose	Population	Adverse events
400 mg 1 times / day multiple, oral Recommended	healthy, 35.56 years (range: 18-45 years) n = 12	Other AEs: Creatine phosphokinase increased, Rash...

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AEs

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AE	Significance	Dose	Population
Creatine phosphokinase increased	1 patient	400 mg 1 times / day multiple, oral Recommended	healthy, 35.56 years (range: 18-45 years) n = 12
Rash	1 patient	400 mg 1 times / day multiple, oral Recommended	healthy, 35.56 years (range: 18-45 years) n = 12

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Sourcing

Sourcing

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Vendor/Aggregator	ID	URL
ChEBI	CHEBI:85083	https://www.ebi.ac.uk/chebi/searchId.do?chebiId=CHEBI:85083
ZINC	ZINC000100074252	http://zinc15.docking.org/substances/ZINC000100074252

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PubMed

Show entries

Title	Date	PubMed
The combination of alisporivir plus an NS5A inhibitor provides additive to synergistic anti-hepatitis C virus activity without detectable cross-resistance.	2014 Jun	24687498
Changing the face of hepatitis C management - the design and development of sofosbuvir.	2015	25987834
Interferon-free therapy for hepatitis C: The hurdles amid a golden era.	2015 Sep	25937625

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Patents

Sample Use Guides

In Vivo Use Guide

The recommended dosage of SOVALDI is one 400 mg tablet, taken orally, once daily with or without food.

Route of Administration: Oral

In Vitro Use Guide

In HCV replicon assays, the EC50 values of sofosbuvir against full-length replicons from genotype 1a, 1b, 2a, 3a and 4a, and chimeric 1b replicons encoding NS5B from genotype 2b, 5a or 6a ranged from 0.014 to 0.11 micromolar. The median EC50 value of sofosbuvir against chimeric replicons encoding NS5B sequences from clinical isolates was 0.062 micromolar for genotype 1a (range 0.029–0.128 micromolar; N=67), 0.102 micromolar for genotype 1b (range 0.045–0.170 micromolar; N=29), 0.029 micromolar for genotype 2 (range 0.014–0.081 micromolar; N=15) and 0.081 micromolar for genotype 3a (range 0.024–0.181 micromolar; N=106). In infectious virus assays, the EC50 values of sofosbuvir against genotype 1a and 2a were 0.03 and 0.02 micromolar, respectively. The presence of 40% human serum had no effect on the anti-HCV activity of sofosbuvir. Evaluation of sofosbuvir in combination with interferon alpha or ribavirin showed no antagonistic effect in reducing HCV RNA levels in replicon cells.