Exploring the fatty acid amide hydrolase and cyclooxygenase inhibitory properties of novel amide derivatives of ibuprofen

Inhibition of fatty acid amide hydrolase (FAAH) reduces the gastrointestinal damage produced by non-steroidal anti-inflammatory agents such as sulindac and indomethacin in experimental animals, suggesting that a dual-action FAAH-cyclooxygenase (COX) inhibitor could have useful therapeutic properties. Here, we have investigated 12 novel amide analogues of ibuprofen as potential dual-action FAAH/COX inhibitors. N-(3-Bromopyridin-2-yl)−2-(4-isobutylphenyl)propanamide (Ibu-AM68) was found to inhibit the hydrolysis of [3H]anandamide by rat brain homogenates by a reversible, mixed-type mechanism of inhibition with a Ki value of 0.26 µM and an α value of 4.9. At a concentration of 10 µM, the compound did not inhibit the cyclooxygenation of arachidonic acid by either ovine COX-1 or human recombinant COX-2. However, this concentration of Ibu-AM68 greatly reduced the ability of the COX-2 to catalyse the cyclooxygenation of the endocannabinoid 2-arachidonoylglycerol. It is concluded that Ibu-AM68 is a dual-acting FAAH/substrate-selective COX inhibitor

Design and pharmacological evaluation of Ibuprofen amides derivatives as dual FAAH/COX inhibitors

Fatty acid amide hydrolase (FAAH) is a serine hydrolase enzyme responsible of the hydrolytic degradation of N-acylethanolamine endocannabinoids, such as the Arachidonoylethanolamide (anandamide, AEA), which it has been shown to alleviate pain and inflammation (1). In particular, the anti-nociceptive and anti-inflammatory effects of AEA could be enhanced by the simultaneous block of FAAH and COX enzymes (2). For this reason, several studies have been carried out in order to develop new FAAH/COX inhibitors (2). In 1997 it was reported that the NSAID ibuprofen inhibited FAAH, although with a modest potency (3), and successively the first dual inibhitor, the amide derivative of ibuprofen with a 2-amino-3-methylpyridine side chain (Ibu-AM5) was reported (4). -5). Benzylamides and piperazinoamides analogs of Ibuprofen have been also designed as less potent FAAH inhibitors than Ibu-AM5 (5). Here, I discuss the computational studies and the structure–activity relationships leading to the design, of novel Ibuprofen amide derivatives with a higher inhibition potency of FAAH and COX, which represent novel powerful anti-nociceptive agents

Risk Factor Analysis of Bird Beak Occurrence after Thoracic Endovascular Aortic Repair

ObjectivesThe aim was to analyze the role played by anatomy and stent graft in the incidence of incomplete apposition to aortic arch.MethodsBetween 2007 and 2014 data including available and suitable computed tomographic angiography (CTA) imaging of patients who had undergone thoracic endovascular aortic repair were reviewed. The study included 80 patients (65 men, 54 ± 21 years) treated for traumatic aortic rupture (n = 27), thoracic aortic aneurysm (n = 15), type B aortic dissection (n = 24), penetrating aortic ulcer (n = 5), intramural hematoma (n = 2), aorto-oesophageal fistula (n = 2), and aortic mural thrombus (n = 5). Pre- and post-operative CTA images were analyzed to characterize bird beak in terms of length and angle, and to calculate aortic angulation within a 30 mm range at the proximal deployment zone.ResultsBird beak configuration was detected in 46 patients (57%): mean stent protrusion length was 16 mm (range: 8–29 mm) and mean bird beak angle was 20° (range: 7–40°). The bird beak effect was significantly more frequent after traumatic aortic rupture treatment (p = .05) and in landing zone 2 (p = .01). No influence of either stent graft type or generation, or degree of oversizing was observed (p = .29, p = .28, p = .81 respectively). However, the mean aortic angle of patients with bird beak was higher in the Pro-form group than that in the Zenith TX2 group (62° vs. 48°, p = .13). Multivariate analysis identified the aortic angle of the deployment zone as the unique independent risk factor of malapposition (HR = 1.05, 95% CI 1–1.10, p = .005). The cutoff value of 51° was found to be predictive of bird beak occurrence with a sensitivity of 58% and a specificity of 85%.ConclusionsAssessment of proximal landing zone morphology to avoid deployment zones generating an aortic angle of over 50° can be recommended to improve aortic curvature apposition with the current available devices

Investigating the role of Cu-oxo species in Cu-nitrate formation over Cu-CHA catalysts

The speciation of framework-interacting Cu(II) sites in Cu-chabazite zeolite catalysts active in the selective catalytic reduction of NO(x) with NH(3) is studied, to investigate the influence of the Al content on the copper structure and their reactivity towards a NO/O(2) mixture. To this aim, three samples with similar Cu densities and different Si/Al ratios (5, 15 and 29) were studied using in situ X-ray absorption spectroscopy (XAS), FTIR and diffuse reflectance UV-Vis during pretreatment in O(2) followed by the reaction. XAS and UV-Vis data clearly show the main presence of Z(2)Cu(II) sites (with Z representing a framework negative charge) at a low Si/Al ratio, as predicted. EXAFS wavelet transform analysis showed a non-negligible fraction of proximal Z(2)Cu(II) monomers, possibly stabilized into two 6-membered rings within the same cage. These sites are not able to form Cu-nitrates by interaction with NO/O(2). By contrast, framework-anchored Z[Cu(II)(NO(3))] complexes with a chelating bidentate structure are formed in samples with a higher Si/Al ratio, by reaction of NO/O(2) with Z[Cu(II)(OH)] sites or structurally similar mono- or multi-copper Z(x)[Cu(II)(x)O(y)] sites. Linear combination fit (LCF) analysis of the XAS data showed good agreement between the fraction of Z[Cu(II)(OH)]/Z(x)[Cu(II)(x)O(y)] sites formed during activation in O(2) and that of Z[Cu(II)(NO(3))] complexes formed by reaction with NO/O(2), further confirming the chemical inertia of Z(2)Cu(II) towards these reactants in the absence of solvating NH(3) molecules

From: Trash to resource: Recovered-Pd from spent three-way catalysts as a precursor of an effective photo-catalyst for H2 production

The successful production of a nanostructured and highly dispersed Pd-TiO2 photo-catalyst, using [Pd(Me2dazdt)2](I3)2 (Me2dazdt = N,N\u2032-dimethyl-perhydrodiazepine-2,3-dithione) salt, obtained through the selective and safe recovery of palladium from model exhaust three-way catalysts (TWCs), is reported here. The photo-catalyst prepared by the impregnation/photo-reduction of palladium on the support showed improved performance in H2 production from methanol and in glycerol photo-reforming compared to reference photo-catalysts obtained from conventional Pd-salts. The reported results represent a case of successful palladium \u201crecovery and re-employment\u201d and thus constitute an example of green chemistry by providing, in one route, the environmentally friendly recovery of a critical metal and its employment in the renewable energy field

Design, synthesis and in vitro and in vivo biological evaluation of flurbiprofen amides as new fatty acid amide hydrolase/cyclooxygenase-2 dual inhibitory potential analgesic agents

Compounds combining dual inhibitory action against FAAH and cyclooxygenase (COX) may be potentially useful analgesics. Here, we describe a novel flurbiprofen analogue, N-(3-bromopyridin-2-yl)-2-(2-fluoro-(1,1'-biphenyl)-4-yl)propanamide (Flu-AM4). The compound is a competitive, reversible inhibitor of FAAH with a Ki value of 13 nM and which inhibits COX activity in a substrate-selective manner. Molecular modelling suggested that Flu-AM4 optimally fits a hydrophobic pocket in the ACB region of FAAH, and binds to COX-2 similarly to flurbiprofen. In vivo studies indicated that at a dose of 10 mg/kg, Flu-AM4 was active in models of prolonged (formalin) and neuropathic (chronic constriction injury) pain and reduced the spinal expression of iNOS, COX-2, and NFκB in the neuropathic model. Thus, the present study identifies Flu-AM4 as a dual-action FAAH/substrate-selective COX inhibitor with anti-inflammatory and analgesic activity in animal pain models. These findings underscore the potential usefulness of such dual-action compounds

Assessing the Influence of Zeolite Composition on Oxygen-Bridged Diamino Dicopper(II) Complexes in Cu-CHA DeNOx Catalysts by Machine Learning-Assisted X-ray Absorption Spectroscopy

[Image: see text] Cu-exchanged chabazite is the catalyst of choice for NO(x) abatement in diesel vehicles aftertreatment systems via ammonia-assisted selective catalytic reduction (NH(3)–SCR). Herein, we exploit in situ X-ray absorption spectroscopy powered by wavelet transform analysis and machine learning-assisted fitting to assess the impact of the zeolite composition on NH(3)-mobilized Cu-complexes formed during the reduction and oxidation half-cycles in NH(3)–SCR at 200 °C. Comparatively analyzing well-characterized Cu-CHA catalysts, we show that the Si/Al ratio of the zeolite host affects the structure of mobile dicopper(II) complexes formed during the oxidation of the [Cu(I)(NH(3))(2)](+) complexes by O(2). Al-rich zeolites promote a planar coordination motif with longer Cu–Cu interatomic distances, while at higher Si/Al values, a bent motif with shorter internuclear separations is also observed. This is paralleled by a more efficient oxidation at a given volumetric Cu density at lower Si/Al, beneficial for the NO(x) conversion under NH(3)–SCR conditions at 200 °C

Halogenated triazinediones behave as antagonists of PKR1: in vitro and in vivo pharmacological characterization

Different prokineticin receptor antagonists, based on the triazinedione scaffold, were synthesized by a new efficient method. Here we demonstrated that 5-benzyltriazinedionessubstituted in position para of the benzyl group with halogens provide compounds endowed with interesting selectivity for the Prokineticin receptor 1 (PKR1). BRET technology indicates that such substitutionresults in increased affinity for thePKR1.The affinity for PKR2, always in M range, was never significantly affected by the para-halogen-benzyl pharmacophores. The analog bearing a para-bromobenzyl pharmacophore (PC-25) displayed the highest affinity for PKR1 (~18 times higher than the reference PC-1 that bears apara-ethyl benzyl group) and the highest selectivity (~300 times). The other halogen substitutedanalogs (PC-7, PC-18 and PC-35), showed selectivity for PKR1 more than 100 times higher than for PKR2. Using transgenic mice lacking one of the two PKRs we demonstrated that all these compounds were able to abolish the Bv8-induced hyperalgesia in mice still expressing the PKR1 at doses lower than those necessary to abolish hyperalgesia in mice expressing only the PKR2. The dose ratio reflected the in- vitro evaluated receptor selectivity

Performance of the LHCb muon system with cosmic rays

The LHCb Muon system performance is presented using cosmic ray events collected in 2009. These events allowed to test and optimize the detector configuration before the LHC start. The space and time alignment and the measurement of chamber efficiency, time resolution and cluster size are described in detail. The results are in agreement with the expected detector performance.Comment: Submitted to JINST and accepte