Raltegravir, elvitegravir, and metoogravir: the birth of "me-too" HIV-1 integrase inhibitors

Merck's MK-0518, known as raltegravir, has recently become the first FDA-approved HIV-1 integrase (IN) inhibitor and has since risen to blockbuster drug status. Much research has in turn been conducted over the last few years aimed at recreating but optimizing the compound's interactions with the protein. Resulting me-too drugs have shown favorable pharmacokinetic properties and appear drug-like but, as expected, most have a highly similar interaction with IN to that of raltegravir. We propose that, based upon conclusions drawn from our docking studies illustrated herein, most of these me-too MK-0518 analogues may experience a low success rate against raltegravir-resistant HIV strains. As HIV has a very high mutational competence, the development of drugs with new mechanisms of inhibitory action and/or new active substituents may be a more successful route to take in the development of second- and third-generation IN inhibitors

Hydrated copper and gold monovalent cations: Ab initio study

To understand the hydration phenomena of noble transition metals, we investigated the structures, hydration energies, electronic properties, and spectra of the Cu+(H3O)(1-6) and Au+ (H2O)(1-6) clusters using ab initio calculations. The coordination numbers of these clusters are found to be only two, which is highly contrasted to those of Ag+ (H2O)(n) (which have the coordination numbers of 3-4) as well as the hydrated alkali metal ions (which have the coordination numbers of similar to6). For the possible identification of their interesting hydration structures, we predict their IR spectra for the OH stretch modes. (C) 2005 American Institute of Physics.open384

Discovery of Novel CXCR2 Inhibitors Using Ligand-Based Pharmacophore Models

The chemokine receptor CXCR2 is expressed on various immune cells and is essential for neutrophil recruitment and angiogenesis at sites of acute and chronic inflammation caused by tissue injury or infection. CXCR2 and its ligand, CXCL8, are implicated in a number of inflammation-mediated diseases such as chronic obstructive pulmonary disease, cystic fibrosis, and cancer. Though the development of CXCR2-specific small-molecule inhibitors as anti-inflammatory agents has been pursued by pharmaceutical companies within the past decade, there are currently no clinically approved CXCR2 inhibitors. A pharmacophore model based on previously reported CXCR2 antagonists was developed to screen a database of commercially available compounds. Small-molecule compounds identified from the pharmacophore screening were selected for in vitro screening in a cell-based CXCR2-mediated β-arrestin-2 recruitment assay and further characterized in several cell-based assays and lipopolysaccharide (LPS)-induced lung inflammation studies in mice. CX compounds identified from pharmacophore modeling inhibited cell migration, lung and colon cancer cell proliferation, and colony formation. Mechanistic studies of CX4152 showed that this compound inhibits CXCR2 signaling through downregulation of surface CXCR2. Additionally, CX4152 significantly inhibits CXCL8-mediated neutrophil migration and LPS-induced lung inflammation in mice. Using a CXCR2-inhibitor-based pharmacophore model, we identified a novel set of sulfonamides from a diverse library of small molecules. These compounds inhibit CXCR2/β-arrestin-2 association, cell migration and proliferation, and acute inflammation in mouse models. CX compounds identified from our pharmacophore models are potential leads for further optimization and development as anti-inflammatory and anticancer agents

Discovery of Novel CXCR2 Inhibitors Using Ligand-Based Pharmacophore Models

The chemokine receptor CXCR2 is expressed on various immune cells and is essential for neutrophil recruitment and angiogenesis at sites of acute and chronic inflammation caused by tissue injury or infection. CXCR2 and its ligand, CXCL8, are implicated in a number of inflammation-mediated diseases such as chronic obstructive pulmonary disease, cystic fibrosis, and cancer. Though the development of CXCR2-specific small-molecule inhibitors as anti-inflammatory agents has been pursued by pharmaceutical companies within the past decade, there are currently no clinically approved CXCR2 inhibitors. A pharmacophore model based on previously reported CXCR2 antagonists was developed to screen a database of commercially available compounds. Small-molecule compounds identified from the pharmacophore screening were selected for in vitro screening in a cell-based CXCR2-mediated β-arrestin-2 recruitment assay and further characterized in several cell-based assays and lipopolysaccharide (LPS)-induced lung inflammation studies in mice. CX compounds identified from pharmacophore modeling inhibited cell migration, lung and colon cancer cell proliferation, and colony formation. Mechanistic studies of CX4152 showed that this compound inhibits CXCR2 signaling through downregulation of surface CXCR2. Additionally, CX4152 significantly inhibits CXCL8-mediated neutrophil migration and LPS-induced lung inflammation in mice. Using a CXCR2-inhibitor-based pharmacophore model, we identified a novel set of sulfonamides from a diverse library of small molecules. These compounds inhibit CXCR2/β-arrestin-2 association, cell migration and proliferation, and acute inflammation in mouse models. CX compounds identified from our pharmacophore models are potential leads for further optimization and development as anti-inflammatory and anticancer agents

Design, Synthesis and Structure-activity Studies of Rhodanine Derivatives as HIV-1 Integrase Inhibitors

Raltegravir was the first HIV-1 integrase inhibitor that gained FDA approval for use in the treatment of HIV-1 infection. Because of the emergence of IN inhibitor-resistant viral strains, there is a need to identify innovative second-generation IN inhibitors. Previously, we identified 2-thioxo-4-thiazolidinone (rhodanine)-containing compounds as IN inhibitors. Herein, we report the design, synthesis and docking studies of a series of novel rhodanine derivatives as IN inhibitors. All these compounds were further tested against human apurinic/apyrimidinic endonuclease 1 (APE1) to determine their selectivity. Two compounds showed significant cytotoxicity in a panel of human cancer cell lines. Taken together, our results show that rhodanines are a promising class of compounds for developing drugs with antiviral and anticancer properties