s-1360 and HIV-Infections

Shionogi and GlaxoSmithKline, as the joint venture company Shionogi-GlaxoSmithKline Pharmaceuticals, is developing S-1360, an HIV integrase inhibitor as a potential treatment for HIV infection. As of October 2002, phase II trials were ongoing and launch is expected in 2004/2005.

Topics: Anti-HIV Agents; Clinical Trials, Phase I as Topic; Clinical Trials, Phase II as Topic; Furans; HIV Infections; HIV Integrase Inhibitors; Humans; Triazoles

Human immunodeficiency virus type-1 (HIV-1) integrase is one of the three virally encoded enzymes required for replication and therefore a rational target for chemotherapeutic intervention in the treatment of HIV-1 infection. We report here the discovery of Raltegravir, the first HIV-integrase inhibitor approved by FDA for the treatment of HIV infection. It derives from the evolution of 5,6-dihydroxypyrimidine-4-carboxamides and N-methyl-4-hydroxypyrimidinone-carboxamides, which exhibited potent inhibition of the HIV-integrase catalyzed strand transfer process. Structural modifications on these molecules were made in order to maximize potency as HIV-integrase inhibitors against the wild type virus, a selection of mutants, and optimize the selectivity, pharmacokinetic, and metabolic profiles in preclinical species. The good profile of Raltegravir has enabled its progression toward the end of phase III clinical trials for the treatment of HIV-1 infection and culminated with the FDA approval as the first HIV-integrase inhibitor for the treatment of HIV-1 infection.

Topics: Administration, Oral; Area Under Curve; Biological Availability; Half-Life; HIV Infections; HIV Integrase Inhibitors; Humans; Magnetic Resonance Spectroscopy; Mass Spectrometry; Pyrrolidinones; Raltegravir Potassium

Study of HIV-1 resistance development to the diketo analogue S-1360, the first HIV-1 integrase strand transfer inhibitor that has entered clinical development.. HIV-1(IIIB) was passaged in cell culture in the presence of increasing concentrations of S-1360 (IIIB/S-1360(res)).. The IIIB/S-1360(res) strains selected for 30, 50 and 70 passages in the presence of S-1360 were evaluated genotypically by sequencing analysis and phenotypically using the MT-4/MTT assay.. Multiple mutations, nine in total, emerged progressively in the catalytic domain of integrase as a result of the selection process. They included T66I and L74M that have both been associated with resistance against the diketo acid L-708,906. After 30, 50 and 70 passages in the presence of S-1360, IIIB/S-1360(res) displayed a four-, eight- and more than 62-fold reduced susceptibility for S-1360, respectively. Phenotypic cross-resistance to L-708,906 was modest for the IIIB/S-1360(res) strain selected during 50 passages, but pronounced for the strain selected during 70 passages. Interesting, all IIIB/S-1360(res) strains remained fully susceptible to the pyranodipyrimidine V-165, an integrase DNA binding inhibitor. Recombination of the mutant integrase genes into wild-type background by integrase-chimeric virus technology entirely reproduced the resistance profile of the IIIB/S-1360(res) strains. As for the replication kinetics of the selected and recombined strains, reduced replication fitness was measured for all strains when compared with their respective wild-type strains.. The accumulation of integrase mutations coincided with an increasing level of (cross-)resistance of IIIB/S-1360(res). Integrase-chimeric virus technology confirmed that the integrase mutations are indeed fully responsible for the resistance phenotype of IIIB/S-1360.

Topics: Anti-HIV Agents; Cells, Cultured; Clone Cells; Drug Resistance, Viral; Furans; HIV Infections; HIV Integrase; HIV-1; Humans; Mutation; Phenotype; Polymerase Chain Reaction; Triazoles; Virus Replication

Topics: Anti-HIV Agents; CCR5 Receptor Antagonists; Clinical Trials as Topic; Cyclic N-Oxides; Drugs, Investigational; Enfuvirtide; Furans; HIV; HIV Envelope Protein gp120; HIV Envelope Protein gp41; HIV Infections; HIV Integrase Inhibitors; Humans; Nitriles; Oximes; Peptide Fragments; Piperazines; Piperidines; Pyridazines; Pyridines; Pyrimidines; Reverse Transcriptase Inhibitors; Triazoles