Search results for "pyridazine"
showing 10 items of 69 documents
Kinase Inhibitors in Multitargeted Cancer Therapy
2017
The old-fashioned anticancer approaches, aiming in arresting cancer cell proliferation interfering with non-specific targets (e.g. DNA), have been replaced, in the last decades, by more specific target oriented ones. Nonetheless, single-target approaches have not always led to optimal outcomes because, for its complexity, cancer needs to be tackled at various levels by modulation of several targets. Although at present, combinations of individual single-target drugs represent the most clinically practiced therapeutic approaches, the modulation of multiple proteins by a single drug, in accordance with the polypharmacological strategy, has become more and more appealing. In the perspective of…
PI3K inhibition reduces murine and human liver fibrogenesis in precisioncut liver slices
2019
Background: Liver fibrosis results from continuous inflammation and injury. Despite its high prevalence worldwide, no approved antifibrotic therapies exist. Omipalisib is a selective inhibitor of the PI3K/mTOR pathway that controls nutrient metabolism, growth and proliferation. It has shown antifibrotic properties in vitro. While clinical trials for idiopathic pulmonary fibrosis have been initiated, an in-depth preclinical evaluation is lacking. We evaluated omipalisib's effects on fibrogenesis using the ex vivo model of murine and human precision-cut tissue slices (PCTS).Methods: Murine and human liver and jejunum PCTS were incubated with omipalisib up to 10 mu M for 48 h. PI3K pathway act…
Levosimendan protects human hepatocytes from ischemia-reperfusion injury.
2017
Background Ischemia-reperfusion injury (IRI) is a major challenge in liver transplantation. The mitochondrial pathway plays a pivotal role in hepatic IRI. Levosimendan, a calcium channel sensitizer, was shown to attenuate apoptosis after IRI in animal livers. The aim of this study was to investigate the effect of levosimendan on apoptosis in human hepatocytes. Methods Primary human hepatocytes were either exposed to hypoxia or cultured under normoxic conditions. After the hypoxic phase, reoxygenation was implemented and cells were treated with different concentrations of levosimendan (10ng/ml, 100ng/ml, 1000ng/ml). The overall metabolic activity of the cells was measured using 3-(4,5-dimeth…
Synthesis of Novel Polyazinyl-Substituted Triazolopyridines from [1,2,3]Triazolo[1,5-a]pyridines
2017
A series of 7-azinyl-substituted triazolopyridines and 3-(6-azinyl-substituted 2-pyridyl)triazolopyridines were synthesized by addition of the corresponding 3-substituted 7-lithiotriazolopyridine to pyrimidine, pyrazine, pyridazine, and 1,3,5-triazine respectively, followed by hydrolysis and oxidation.
Safety and Ergogenic Properties of Combined Aminophylline and Ambrisentan in Hypoxia.
2017
We hypothesized that concomitant pharmacological inhibition of the endothelin and adenosine pathway is safe and improves exercise performance in hypoxic humans, via a mechanism that does not involve augmentation of blood oxygenation. To test this hypothesis, we established safety and drug interactions for aminophylline (500 mg) plus ambrisentan (5 mg) in normoxic volunteers. Subsequently, a placebo‐controlled study was employed to test the combination in healthy resting and exercising volunteers at simulated altitude (4,267 m). No serious adverse events occurred. Drug interaction was minimal or absent. Aminophylline alleviated hypoxia‐induced headaches. Aminophylline, ambrisentan, and their…
Pyridazine-Supported Polymeric Cyanometallates with Spin Transitions
2019
Heterometallic cyano-bridged spin-crossover complexes form a large family of switchable compounds with different structural motives and diverse transition characteristics. Here we report on the hysteretic water-dependent spin transitions found in the family of [Fe(pyridazine)2M(CN)4] frameworks (M = Ni, Pd, Pt). The structure of three new spin-crossover compounds is built of cyanometallic layers supported by pyridazine ligands. The frameworks contain water guest molecules that can be removed upon heating. Spin transition was found in both hydrated and dehydrated compounds, while the removal of water stimulated a complete spin state switch. Mössbauer spectroscopy revealed two different …
Anti-Hypotensive Treatment and Endothelin Blockade Synergistically Antagonize Exercise Fatigue in Rats under Simulated High Altitude
2013
Rapid ascent to high altitude causes illness and fatigue, and there is a demand for effective acute treatments to alleviate such effects. We hypothesized that increased oxygen delivery to the tissue using a combination of a hypertensive agent and an endothelin receptor A antagonist drugs would limit exercise-induced fatigue at simulated high altitude. Our data showed that the combination of 0.1 mg/kg ambrisentan with either 20 mg/kg ephedrine or 10 mg/kg methylphenidate significantly improved exercise duration in rats at simulated altitude of 4,267 m, whereas the individual compounds did not. In normoxic, anesthetized rats, ephedrine alone and in combination with ambrisentan increased heart…
Anion-Directed Self-Assembly of Unusual Discrete and One-Dimensional Copper(II) Complexes of 3,6-Bis(2′-pyridyl)pyridazine
2012
The preparation and crystal structures of six new copper(II) compounds of formula [Cu(dppn)2(ClO4)]ClO4 (1), [Cu2(dppn)(OH)(ClO4)3(H2O)3]·H2O (2), [Cu2(dppn)2(H2O)2](ClO4)4 (3), [Cu2(dppn)2(ClO4)4] (4), {[Cu2(dppn)(N3)4]·H2O/[Cu2(dppn)(N3)4(H2O)]}n (5) and {[Cu2(dppn)(OH)(dca)3]·H2O}n (6) [dppn = 3,6-bis(2′-pyridyl)pyridazine and dca = dicyanamide] are reported. 1 is a mononuclear complex where two bidentate dppn molecules and a monodentate perchlorate build an intermediate square pyramidal/trigonal bipyramidal (sp/tbp) five-coordinate environment around the copper(II) ion, the overall positive charge being balanced by a free perchlorate anion. 2–4 are dinuclear complexes with either one (2…
Synthesis, crystal structure, electrochemical and magnetic properties of (NBu4)[ReCl5(L)] with L=pyrimidine and pyridazine
2008
Abstract Two novel rhenium(IV) compounds, namely (NBu4)[ReCl5(pym)] (1) and (NBu4)[ReCl5(pyd)] (2) (pym = pyrimidine, pyd = pyridazine and NBu4 = n-tetrabutylammonium cation), have been obtained by reaction of [ReCl6]2− and the diazine in dmf, and their crystal structures determined by single-crystal X-ray diffraction. The structures of 1 and 2 consist of [ReCl5(pym)]− or [ReCl5(pyd)]− anions and NBu 4 + cations held together by electrostatic forces and van der Waals interactions. Stacking interactions are present only in 1. The coordination sphere of the ReIV ion is defined by five chloride anions and one nitrogen atom of a monodentate diazine, resulting in a distorted octahedral environme…
Ligand effects on the structures and magnetic properties of tricyanomethanide-containing copper(II) complexes.
2007
The preparation, crystal structure and magnetic properties of four heteroleptic copper(II) complexes with the tricyanomethanide (tcm(-)) and the heterocyclic nitrogen donors 3,6-bis(2-pyridyl)pyridazine (dppn), 2,5-bis(2-pyridyl)pyrazine (2,5-dpp), 2,3-bis(2-pyridyl)pyrazine (2,3-dpp) and 2,3-bis(2-pyridyl)quinoxaline (2,3-dpq) are reported, {[Cu(2)(dppn)(OH)(tcm)(2)] x tcm}(n) (1), {[Cu(2,5-dpp)(tcm)] x tcm}(n) (2), {[Cu(2)(2,3-dpp)(2)(tcm)(3)(H(2)O)(0.5)] x tcm x 0.5H(2)O}(n) (3) and [Cu(2,3-dpq)(tcm)(2)](n) (4). 1 has a ladder-like structure with single mu-1,5-tcm ligands forming the sides and a bis-bidentate dppn and a single mu-hydroxo providing the rung. Each copper atom in 1 exhibits…