Introduced to the Market in the Last Decade (2001−2011) Jiang Wang,† María Sańchez-Rosello,́‡,§ Jose ́ Luis Aceña, Carlos del Pozo,‡ Alexander E. Sorochinsky, Santos Fustero,*,‡,§ Vadim A. Soloshonok,* and Hong Liu*,† †Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu Chong Zhi Road, Shanghai 201203, China ‡Department of Organic Chemistry, Faculty of Pharmacy, University of Valencia, Av. Vicente Andreś Estelleś, 46100 Burjassot, Valencia, Spain Laboratorio de Molećulas Orgańicas, Centro de Investigacioń Príncipe Felipe, C/ Eduardo Primo Yuf́era 3, 46012 Valencia, Spain Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel Lardizab́al 3, 20018 San Sebastian, Spain IKERBASQUE, Basque Foundation for Science, Alameda Urquijo, 36-5 Plaza Bizkaia, 48011 Bilbao, Spain Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Sciences of Ukraine, Murmanska Street 1, 02660 Kyiv-94, Ukraine

Fluorine in pharmaceutical industry: fluorine-containing drugs introduced to the market in the last decade (2001-2011).

Kinase inhibitors are a new class of therapeutics with a propensity to inhibit multiple targets. The biological consequences of multi-kinase activity are poorly defined, and an important step toward understanding the relationship between selectivity, efficacy and safety is the exploration of how inhibitors interact with the human kinome. We present interaction maps for 38 kinase inhibitors across a panel of 317 kinases representing >50% of the predicted human protein kinome. The data constitute the most comprehensive study of kinase inhibitor selectivity to date and reveal a wide diversity of interaction patterns. To enable a global analysis of the results, we introduce the concept of a selectivity score as a general tool to quantify and differentiate the observed interaction patterns. We further investigate the impact of panel size and find that small assay panels do not provide a robust measure of selectivity.

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A quantitative analysis of kinase inhibitor selectivity.

We are entering an era in which biological macromolecules can be designed to order and genetically or synthetically produced. If the experience with classical low molecular weight drugs is any guide, it will be possible in fact, easy to produce many more such agents than can be tested for effect in animals, let alone in humans. Predictive criteria are required for the process of rational design, and these must be based on an understanding of fundamental physiological and pharmacological principles. Monoclonal antibodies illustrate the point. Hundreds of new monoclonal reagents with possible clinical use are being developed every year. Each of them could be administered as whole antibody, F(ab')*, or Fab. Each could be conjugated to a toxin, a drug, a radionuclide, or a liposome containing one of those agents. Each could be class-switched to change effector functions or could be mutated in its binding site. As noted previously,' the combinatorial aspects of trying every possibility are out of the question even before one has considered such current and likely future developments as ( I ) chimeric molecules combining mouse variable and human constant domains; (2) Fv (variable domain) fragments; (3) recombinants consisting of murine hypervariable segments and human variable domain framework; (4) conjugates formed by genetically grafting a linker peptide onto the molecule; and (5) enzyme-antibody or toxin-antibody chimeras. At the end of this developmental process will be ligand molecules consisting of antibody-derived binding sites grafted onto molecules designed de novo. A predictive pharmacology of biologicals must be based on theoretical and experimental information from several hierarchical levels: global (whole body), regional, local, cellular, and molecular. Here we will focus on one study of whole body pharmacokinetics, one development in regional delivery, and one issue at the local, or tissue, level.

The pharmacology of monoclonal antibodies.

This review analyses the literature from the early 1990s until the beginning of 2003 and covers the use of carbon nanotubes (CNT) and nanofibers as catalysts and catalysts supports. The article is composed of three sections, the first one explains why these materials can be suitable for these applications, the second describes the different preparation methods for supporting metallic catalysts on these supports, and the last one details the catalytic results obtained with nanotubes or nanofibers based catalysts. When possible, the results were compared to those obtained on classical carbonaceous supports and explanations are proposed to clarify the different behaviors observed.

Carbon nanotubes and nanofibers in catalysis

The method of weighted residuals and variational principles : with application in fluid mechanics, heat and mass transfer

The solution U(t) to the linear differential equation dU/dt = h(t)U can be represented by a finite product of exponential operators; In many interesting cases the representation is global. U(t) = exp[g1(t)H1] exp [g2(t)H2] … exp[gn(t)Hn] where gi(t) are scalar functions and Hi are constant operators. The number, n, of terms in this expansion is equal to the dimension of the Lie algebra generated by H(t). Each term in this product has time‐independent eigenvectors. Some applications of this solution to physical problems are given.

Lie Algebraic Solution of Linear Differential Equations

To improve the antitumor properties and optimize the pharmaceutical properties including solubility and protein binding of indolin-2-ones, a number of different basic and weakly basic analogues were designed and synthesized. 5-[5-Fluoro-2-oxo-1,2-dihydroindol-(3Z)-ylidenemethyl]-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide (12b or SU11248) has been found to show the best overall profile in terms of potency for the VEGF-R2 and PDGF-Rbeta tyrosine kinase at biochemical and cellular levels, solubility, protein binding, and bioavailability. 12b is currently in phase I clinical trials for the treatment of cancers.

Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase.

We have prepared a novel material, consisting of Pt particles supported on purified single-walled carbon nanotubes (SWNTs), representing the first reported metal-loaded SWNT material. The material contains 10 wt % Pt on entangled SWNT bundles consisting of 20−100 nanotubes each. The average Pt particle size is 1−2 nm. High-resolution transmission electron microscopy (HRTEM) observations combined with electron energy-loss spectroscopy (EELS) indicate chemical bonding between Pt and the SWNT surfaces. This bonding is accomplished presumably by ion exchange on carboxylic acid sites created on the nanotube surfaces by slow wet oxidation in dilute HNO3. In addition, a simple SWNT purification scheme requiring no filtration was developed for the preparation of this material. The purification results in a well-defined structure for the metal support useful for investigating the role of this material as a heterogeneous catalyst and the effects of metal−support interactions (MSI). Preliminary kinetics measurements...

Method for Supporting Platinum on Single-Walled Carbon Nanotubes for a Selective Hydrogenation Catalyst

Diffusion mechanism of hydrocarbons in zeolites—I. Theory

Summary The hydraulic conductivity of s.c. and hepatocarcinoma tissue was determined by in vivo and in vitro experiments. A single parameter was developed to calculate the ratio of diffusive to convective flux of solutes in the extravascular space. Tissue glycosaminoglycan content and solute molecular weight are the two most important parameters which may determine whether the extravascular transport of solutes occurs predominantly by diffusion or by convection. The analysis has implications for transport of metabolic nutrients and wastes, drugs, hormones, plasma proteins, and viruses in the extravascular space.

https://cancerres.aacrjournals.org/content/canres/34/10/2814.full.pdf

James Wei

Papers

Lie Algebraic Solution of Linear Differential Equations

Discovery of 5-[5-fluoro-2-oxo-1,2- dihydroindol-(3Z)-ylidenemethyl]-2,4- dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)amide, a novel tyrosine kinase inhibitor targeting vascular endothelial and platelet-derived growth factor receptor tyrosine kinase.

Method for Supporting Platinum on Single-Walled Carbon Nanotubes for a Selective Hydrogenation Catalyst

Diffusion mechanism of hydrocarbons in zeolites—I. Theory

Diffusion and Convection in Normal and Neoplastic Tissues