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The SARfaris: GPCR, Kinase, ADME

Saturday, 21 September 2013

New Drug Approvals 2013 - Pt. XIII - Dolutegravir (TivicayTM)

ATC code: J05AX12

On 12 August, the FDA approved a further drug for the treatment of HIV-1 infection, Dolutegravir (Tradename: Tivicay). Dolutegravir also known as S/GSK-1349575, is an HIV-1 integrase inhibitor. The drug has been approved for treatment of treatment-naïve as well as treatment-experienced HIV-infected adults including those who have been treated with other integrase inhibitors. In addition, Dolutegravir can be used for the treatment of children aged 12 years or older and weighing at least 40kg who have not been treated with integrase inhibitors, but are either treatment-naïve or treatment –experienced.

HIV, a lentivirus, infects vital cells in the human immune system such as helper T. cells (CD4+ T cells) and macrophages. The disease is responsible for millions of death every year, especially in Sub-Saharan Africa where treatment complications are enhanced by co-infection with tuberculosis and poverty. The approval of a new antiviral agent like Dolutegravir, will enhance treatment of the disease and improve the quality of people’s lives.

Dolutegravir is an inhibitor of HIV-1 integrase responsible for the insertion of the viral DNA into the host chromosomal DNA. The drug interferes with replication of HIV by preventing the viral DNA from assimilating into the genetic material of the human T cells. An example of a 3D structure of the enzyme’s core domain (PDBe: 3vqa) is shown below.

HIV-1 integrase (ChEMBLID: CHEMBL3471, UniProt Accession: Q72498)  is an attractive target for drug design. It is one of three enzymes of HIV (others are Reverse Transcriptase and the Protease) that consists of three main domains with specific functions. The N-terminal domain characterized by the His2Cys2 motif chelates zinc, the core domain consists of the catalytic DDE motif important for the activity of the enzyme, and the C-terminal domain, with an SH3-like fold, that binds DNA nonspecifically. There are a variety of crystal structures of the different domains of HIV-1 integrase reported in PDBe (Protein Data Bank in Europe)

Dolutegravir , ChEMBLID: CHEMBL1229211 (C20H19F2N3O5, IUPAC Name: (4R,12aS)-N-[(2,4-difluorophenyl)methyl]-7-hydroxy-4-methyl-6,8-dioxo-3,4,12,12a-tetrahydro-2H-pyrido[5,6]pyrazino[2,6-b][1,3]oxazine-9-carboxamide, Canonical smiles: CC1CCOC2N1C(=O)C3=C(C(=O)C(=CN3C2)C(=O)NCC4=C(C=C(C=C4)F)F)O) has two chiral centers, molecular weight of 419.12, 2 hydrogen bond donors, 6 hydrogen bond acceptors, 3 rotatable bonds, Polar surface area of 99.18 and alogP of 0.3. Dolutergravir is orally administered since it does not violate Lipinsik’s ‘Rule of Five’. The drug may be taken with or without food. For treatment-naïve or treatment-experienced with integrase transfer inhibitor (INSTI) – naïve adults and children the recommended dose is 50mg once. A dose of 50mg twice daily is recommended when dolutegravir is co-administered with potent UGT1A/CYP3A inducers like efavirenz, fosamprenavir/ritonavir, Tipranavir/ritonavir or rifampin.

The license holder for Dolutegravir is ViiV Healthcare, an HIV joint venture between GSK, Pfizer Inc and Shionogi. The full prescribing information can be found here.

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