Search results for "Zole"
showing 10 items of 2482 documents
Synthesis of alkyl-5,8-dimethyl-6-phenyl-5,6-dihydropyrazolo[3,4-f] [1,2,3,5]tetrazepin-4(3H)-ones of pharmaceutical interest
2006
The multistep synthesis of two pyrazolo[3,4-f][1,2,3,5]tetrazepin-4(3H)-one derivatives, a new class of fused 1,2,3,5-tetrazepinones with potential antiproliferative activity, has been carried out. Owing to the instability of the above compounds, the last step of the synthesis was performed at -5/0 degrees C. The obtained tetrazepinones, when allowed to stand at r.t. for 24 h, afforded quantitatively 1-phenyl-3,6-dimethylpyrazolo [3,4-d][1,2,3] triazole.
Synthesis of pyrazolo[4,3-c][1,2,6]benzothiadiazocine, a new ring system as potential COX inhibitor
2012
Derivatives of the new ring system 1,4-dihydropyrazolo[4,3-c][1,2,6] benzothiadiazocin-11(10H)one 5,5-dioxide were synthesized in five or six steps in 57-66% overall yields and tested as COX inhibitors.
SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF 7-SUBSTITUTED1-ETHYL-3,4,10-TRIMETHYL-1,10-DIHYDRO-11H-PYRAZOLO(3,4-c)(1,6)BENZODIAZOCIN-11-ONE: A NEW RI…
2004
Derivatives of the title ring system of type 10 were obtained in good yield by fusion of the intermediates 12. Attempt to cyclize the acetylamino derivative 9 under Bischler-Napieralski conditions failed because of the insufficient electronic density in the position 4 of the pyrazole ring created by the adjacent carbonyl moiety. The derivatives of the new ring system, assayed as anxiolytic agents, showed no significant activity.
Synthesis of pyrazole-4-carbohydrazide derivatives of pharmaceutical interest
2003
New 1-phenylor 1-methyl-5-benzamidopyrazole-4-carbohydrazide derivatives were prepared in 70–90% yields from 1-methylor 1-phenyl-6-phenylpyrazolo[3,4-d]1,3-oxazin-4(1H)-one derivatives and hydrazine hydrate. Small quantities of the isomeric 5-aminopyrazole-4-(Nbenzoyl)hydrazides were detected in some reaction mixtures, proving that intramolecular benzoyl migration can take place in the 5-benzamidopyrazole-4-carbohydrazide molecule. The direct formation of pyrazole-4-carbohydrazides from 5-benzamidopyrazole-4-carboxylic acid ethyl esters and hydrazine hydrate was unsuccessful.
Palladium-Catalyzed Direct Arylation of Heteroaromatics with Activated Aryl Chlorides Using a Sterically Relieved Ferrocenyl-Diphosphane
2012
International audience; The palladium-catalyzed direct arylations at C3 or C4 positions of heteroaromatics are known to be more challenging than at C2 or C5 positions. Aryl chlorides are also challenging substrates for direct arylation of heteroaromatics. We observed that in the presence of a palladium-catalyst combining only 0.5 mol % of Pd(OAc)2 with the sterically relieved new ferrocenyl diphosphane Sylphos, the direct arylation at C3 or C4 of oxazoles, a benzofuran, an indole, and a pyrazole was found to proceed in moderate to high yields using a variety of electron deficient aryl chlorides. Turnover numbers up to 176 have been obtained with this catalyst. Assessment of the electron-don…
Mutant HRAS as novel target for MEK and mTOR inhibitors.
2015
HRAS is a frequently mutated oncogene in cancer. However, mutant HRAS as drug target has not been investigated so far. Here, we show that mutant HRAS hyperactivates the RAS and the mTOR pathway in various cancer cell lines including lung, bladder and esophageal cancer. HRAS mutation sensitized toward growth inhibition by the MEK inhibitors AZD6244, MEK162 and PD0325901. Further, we found that MEK inhibitors induce apoptosis in mutant HRAS cell lines but not in cell lines lacking RAS mutations. In addition, knockdown of HRAS by siRNA blocked cell growth in mutant HRAS cell lines. Inhibition of the PI3K pathway alone or in combination with MEK inhibitors did not alter signaling nor had an imp…
Determination of Drug Concentrations in Serum and Dopamine Receptor Occupancy in Brain for Optimal Antipsychotic Drug Therapy
2009
Evidence has been given that antipsychotic effects of dopamine receptor antagonists are associated with 60 and 80% striatal dopamine D2 and D3 receptor occupancy. Receptor occupancy correlates well with concentrations of the antipsychotic drugs in serum or plasma, much better than the dose. The latter is consistent with weak correlations between antipsychotic dose and serum concentrations and explained by the high interindividual variabilities in drug metabolism. Using positron emission tomography (PET) for in vivo determination of dopamine receptor occupancy in conjunction with drug concentration measurements “therapeutic windows” could be calculated for the atypical antipsychotic drugs am…
Targeting Orthosteric and Allosteric Pockets of Aromatase via Dual-Mode Novel Azole Inhibitors
2020
[Image: see text] Breast cancer (BC) is the most diffused cancer type in women and the second leading cause of death among the female population. Effective strategies to fight estrogen responsive (ER+) BC, which represents 70% of all BC cases, rely on estrogen deprivation, via the inhibition of the aromatase enzyme, or the modulation of its cognate estrogen receptor. Current clinical therapies significantly increased patient survival time. Nevertheless, the onset of resistance in metastatic BC patients undergoing prolonged treatments is becoming a current clinical challenge, urgently demanding to devise innovative strategies. In this context, here we designed, synthesized, and performed in …
Treatment of pulmonary embolism.
2015
International audience; The treatment of pulmonary embolism is going to be deeply modified by the development of Direct Oral Anticoagulants (DOACs). There are currently three anti-Xa factors (rivaroxaban, apixaban, edoxaban) and one anti-IIa factor (dabigatran) labeled by the FDA and the EMA. All these drugs are direct anticoagulant, orally effective, without the need for adaptation to hemostasis test. As kidney excretion is involved for all of them, they are contra-indicated in patients with severe renal failure (creatinine clearance<30mL/min according to Cockcroft & Gault formula). All the anti-Xa factor drugs are metabolized by liver cytochromes and then contra-indicated in case of liver…
Development and biological investigations of hypoxia-sensitive prodrugs of the tyrosine kinase inhibitor crizotinib
2019
Despite the huge success of tyrosine kinase inhibitors as anticancer agents, severe side effects are a major problem. In order to overcome this drawback, the first hypoxia-activatable 2-nitroimidazole-based prodrugs of the clinically approved ALK and c-MET inhibitor crizotinib were developed. The 2-aminopyridine functionality of crizotinib (essential for target kinase binding) was considered as ideal position for prodrug derivatization. Consequently, two different prodrugs were synthesized with the nitroimidazole unit attached to crizotinib either via carbamoylation (A) or alkylation (B) of the 2-aminopyridine moiety. The successful prodrug design could be proven by docking studies and a dr…