Evolution of a novel orally bioavailable series of PI3Kδ inhibitors from an inhaled lead for the treatment of respiratory disease.

A four step process of high quality modelling of existing data, deconstruction, identification of replacement cores and an innovative synthetic re-growth strategy led to the rapid discovery of a novel oral series of PI3K δ inhibitors with promising selectivity and excellent in vivo characteristics

Design, Synthesis, and Evaluation of Lung-Retentive Prodrugs for Extending the Lung Tissue Retention of Inhaled Drugs

A major limitation of pulmonary delivery is that drugs can exhibit suboptimal pharmacokinetic profiles resulting from rapid elimination from the pulmonary tissue. This can lead to systemic side effects and a short duration of action. A series of dibasic dipeptides attached to the poorly lung-retentive muscarinic M3 receptor antagonist piperidin-4-yl 2-hydroxy-2,2-diphenylacetate (1) through a pH-sensitive-linking group have been evaluated. Extensive optimization resulted in 1-(((R)-2-((S)-2,6-diaminohexanamido)-3,3-dimethylbutanoyl)oxy)ethyl 4-(2-hydroxy-2,2-diphenylacetoxy)piperidine-1-carboxylate (23), which combined very good in vitro stability and very high rat lung binding. Compound 23 progressed to pharmacokinetic studies in rats, where, at 24 h post dosing in the rat lung, the total lung concentration of 23 was 31.2 μM. In addition, high levels of liberated drug 1 were still detected locally, demonstrating the benefit of this novel prodrug approach for increasing the apparent pharmacokinetic half-life of drugs in the lungs following pulmonary dosing

Translational pharmacology of an inhaled small molecule αvβ6 integrin inhibitor for idiopathic pulmonary fibrosis

The αvβ6 integrin plays a key role in the activation of transforming growth factor-β (TGFβ), a pro-fibrotic mediator that is pivotal to the development of idiopathic pulmonary fibrosis (IPF). We identified a selective small molecule αvβ6 RGD-mimetic, GSK3008348, and profiled it in a range of disease relevant pre-clinical systems. To understand the relationship between target engagement and inhibition of fibrosis, we measured pharmacodynamic and diseaserelated end points. Here we report, GSK3008348 binds to αvβ6 with high affinity in human IPF lung and reduces downstream pro-fibrotic TGFβ signaling to normal levels. In human lung epithelial cells, GSK3008348 induces rapid internalization and lysosomal degradation of the αvβ6 integrin. In the murine bleomycin-induced lung fibrosis model, GSK3008348 engages αvβ6, induces prolonged inhibition of TGFβ signaling and reduces lung collagen deposition and serum C3M, a marker of IPF disease progression. These studies highlight the potential of inhaled GSK3008348 as an anti-fibrotic therapy

Palladium nanoparticles supported on polyvinylpyridine: Catalyticactivity in Heck-type reactions and XPS structural studies

Palladium nanoparticles, obtained by metal vapour synthesis (MVS), weredeposited on cross-linked polyvinylpyridine. The Pd/PVPy system showedhigh catalytic activity in the Heck C-C coupling reaction of iodo- andbromo-arenes (iodobenzene, bromobenzene, p-nitrobromobenzene,p-bromoacetophenone, p-(methoxy)bromobenzene) with alkyl acrylates(methyl acrylate, n-butyl acrylate, ethylhexyltrans-3-(4-methoxyphenyl)acrylate) at 100 degrees C-175 degrees Cworking under nitrogen atmosphere as well as in air. The catalyst isstable and the leaching of metal in solution is very low. When reused,the recovered Pd/PVPy maintains the catalytic activity of the pristinematerial. XPS structural studies performed on the starting catalyst aswell as on the recovered one indicate the presence of a interactionbetween the basic nitrogen of the pyridine present in the polymer andthe metal. (C) 2009 Elsevier Inc. All rights reserved

New monodispersed palladium nanoparticles stabilized by poly-(N-vinyl-2-pyrrolidone): Preparation, structural study and catalytic properties

Mesitylene/1-hexene solvated palladium nanoparticles, obtained by metal vapour synthesis (MVS) technique, were stabilized in solution at room temperature with poly-(N-vinyl-2-pyrrolidone) (PVP) and isolated by precipitation with a diethyl ether or THF as brown powder. HRTEM and FT-IR analyses on samples with different Pd/PVP ratio (1%, 5%, 10%, 15%, 20 w/w%) showed palladium nanoparticles with mean diameters limited in the range 1.5–2.5 nm and the presence of competitive intermolecular interactions between C@O groups and palladium atoms on nanoparticle surface. The Pd–PVP systems, dissolved in EtOH solvent, showed excellent catalytic activity and selectivity in the hydrogenation of aliphatic alkynes (1-hexyne, 2-hexyne, 3-hexyne, 3-hexyne-1-ol) to the corresponding (Z)-alkenes. The catalytic activity of Pd–PVP samples, dissolved in 1-methyl-2-pyrrolidinone (NMP), has been also evaluated in the Mizoroki–Heck C–C coupling reaction of iodobenzene and bromo-arenes with butyl acrylate showing high efficiency. Moreover, the catalyst can be quantitatively recovered at the end of the reaction by precipitation with diethyl ether and reused without significant loss of catalytic activity

Chemical Synthesis via Metal Atoms: Preparation and X-Ray Structure of (1,3-eta-3-Cyclo-octa-5,6-dienyl)bis(triphenyl-phosphine)rhodium(I)

Co-condensation of Rh vapour with cyclo-octa-1,5-diene followed by addition of a toluene solution of PPh3 yields the title compound which has been characterized by X-ray crystallography