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The SARfaris: GPCR, Kinase, ADME

Wednesday, 12 February 2014

New Drug Approvals 2013 - Pt. XXIV - Sofosbuvir (Sovaldi ™)

ATC code (stem): J05AB
Wikipedia: Sofosbuvir

On December 6, 2013, the FDA approved sofosbuvir for the treatment of patients with chronic hepatitis C infection. Sofosbuvir is intended for use as a component in combination treatments, depending on the type of hepatitis C either alongside Ribavirin alone, or in combination with both Ribavirin and peginterferon-alpha. Earlier in 2013, the FDA had already approved
Simeprevir for the treatment of this condition.

Hepatitis C is an infectious disease that affects primarily the liver and is caused by the hepatitis C virus (HCV), which belongs to the family of Flaviviridae and has a positive sense single stranded RNA genome of 9,600 nucleotides. Infection is mainly by blood-to-blood contact, through sharing or reuse of syringes or unsterilized medical equipment. Initially, the infection progresses without symptoms, and only becomes apparent in the chronic stages when liver damage leads to symptoms such as bleeding, jaundice, liver cancer and hepatic encephalopathy.

Sofosbuvir is a nucleotide analog inhibitor of the viral RNA polymerase (NS5b, Uniprot genome polyprotein: P26664, 2421-3011, PDB 3hkw). Viral RNA polymerases differ significantly from eukaryotic and bacterial polymerases both in sequence and three-dimensional structure. Thus, sofosbuvir inhibits only the amplification of the viral RNA genome and not endogenous transcription in the host organism by entering the polymerase as a substrate and terminating the transcript chain. The IC50 measured against NS5b ranged between 0.7 and 2.6 micro-molar, depending on the genotpye of the HCV isolate.

Structure of HCV NS5b, genotype 1a generated in pymol from PDB 3hkw.
 Sofosbuvir is a prodrug that is converted to the active form through a mono-phosphorylated intermediate. In contrast to other nucleotide analog inhibitors, the intermediate is formed in a step that cleaves off the groups attached to the phosphate group already present in sofosbuvir. This step is a lot faster than the enzymatic addition of a phosphate group that is required with other nucleotide analogs. The enzymes catalyzing this initial step include the lysosomal protective protein (Uniprot P10619), liver carboxylesterase 1 (Uniprot P23141) and Hint1 (Uniprot P49773). [1]

 Canonical 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)Oc3ccccc3 
Std-InChI: 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

Sofosbuvir is an off-white crystalline substance that is slightly soluble in water. The molecular weight and logP are 529.45 Da and 0.92, respectively. Note the relatively low logP charateristic of nucleotide analog compounds.

The recommended daily dose of sofosbuvir is 400mg in a single tablet. Peak plasma concentration of the active metabolite are reached after 30-120 minutes post administration. The clearance is primarily through the kidney, with a half-life of 0.4 hours for sofosbuvir and 27 hours for its metabolite.  Sofosbuvir is a substrate of P-gp, and therefore inducers of P-gp, such as rifampicin and St John's wort are contraindicated for use with sofosbuvir.

Reported side effects of sofosbuvir include fatigue, headache, nausea, insomnia and anemia.

Sofosbuvir is marketed by Gilead under the name Sovaldi.

[1] Murakami E, Tolstykh T, Bao H, Niu C, Steuer HMM, Bao D, Chang W, Espiritu C, Bansal S, Lam AM, Otto MJ, Sofia MJ, Furman P a: Mechanism of activation of PSI-7851 and its diastereoisomer PSI-7977. J. Biol. Chem. 2010, 285:34337–47.

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