618092-68-5Relevant academic research and scientific papers
Molecular iodine-catalyzed one-pot multicomponent synthesis of 5-amino-4-(arylselanyl)-1H-pyrazoles
Pires, Camila S.,De Oliveira, Daniela H.,Pontel, Maria R.B.,Kazmierczak, Jean C.,Cargnelutti, Roberta,Alves, Diego,Jacob, Raquel G.,Schumacher, Ricardo F.
, p. 2789 - 2798 (2018)
A one-pot iodine-catalyzed multicomponent reaction has been developed for the selective preparation of 5-amino-4-(arylselanyl)-1H-pyrazoles from a diverse array of benzoylacetonitriles, arylhydrazines and diaryl diselenides. The reactions were conducted in MeCN as solvent at reflux temperature under air. The methodology presents a large functional group tolerance to electron-deficient, electron-rich, and bulky substituents and gave the expected products in good to excellent yields. The synthesized 1,3-diphenyl-4-(phenylselanyl)-1H-pyrazol-5-amine was submitted to an oxidative dehydrogenative coupling to produce a diazo compound confirmed by X-ray analysis.
Design, synthesis, and biological activity of urea derivatives as anaplastic lymphoma kinase inhibitors
Boijeaf Gennaes, Gustav,Mologni, Luca,Ahmed, Shaheen,Rajaratnam, Mohanathas,Marin, Oriano,Lindholm, Niko,Viltadi, Michela,Gambacorti-Passerini, Carlo,Scapozza, Leonardo,Yli-Kauhaluoma, Jari
experimental part, p. 1680 - 1692 (2012/01/06)
In anaplastic large-cell lymphomas, chromosomal translocations involving the kinase domain of anaplastic lymphoma kinase (ALK), generally fused to the 5' part of the nucleophosmin gene, produce highly oncogenic ALK fusion proteins that deregulate cell cycle, apoptosis, and differentiation in these cells. Other fusion oncoproteins involving ALK, such as echinoderm microtubule-associated protein-like 4-ALK, were recently found in patients with non-small-cell lung, breast, and colorectal cancers. Recent research has focused on the development of inhibitors for targeted therapy of these ALK-positive tumors. Because kinase inhibitors that target the inactive conformation are thought to be more specific than ATP-targeted inhibitors, we investigated the possibility of using two known inhibitors, doramapimod and sorafenib, which target inactive kinases, to design new urea derivatives as ALK inhibitors. We generated a homology model of ALK in its inactive conformation complexed with doramapimod or sorafenib in its active site. The results elucidated why doramapimod is a weak inhibitor and why sorafenib does not inhibit ALK. Virtual screening of commercially available compounds using the homology model of ALK yielded candidate inhibitors, which were tested using biochemical assays. Herein we present the design, synthesis, biological activity, and structure-activity relationships of a novel series of urea compounds as potent ALK inhibitors. Some compounds showed inhibition of purified ALK in the high nanomolar range and selective antiproliferative activity on ALK-positive cells.
Substituent effects of N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamides on positive allosteric modulation of the metabotropic glutamate-5 receptor in rat cortical astrocytes
De Paulis, Tomas,Hemstapat, Kamondanai,Chen, Yelin,Zhang, Yongqin,Saleh, Samir,Alagille, David,Baldwin, Ronald M.,Tamagnan, Gilles D.,Conn, P. Jeffrey
, p. 3332 - 3344 (2007/10/03)
CDPPB [3-cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide] was recently described as the first centrally active, positive allosteric modulator of rat and human metabotropic glutamate receptor (mGluR) mGluR5 subtype. We explored the structural requirements for potentiation of glutamate-induced calcium release in naturally expressed mGluR5 in cultured rat astrocytes and increasing affinity for the allosteric antagonist binding site by evaluating 50 analogues of CDPPB. In the fluorometric calcium assay, CDPPB exhibited an EC50 value of 77 ± 15 nM in potentiating mGluR 5-mediated responses in cortical astrocytes and a Ki value of 3760 ± 430 nM in displacing [3H]methoxyPEPy binding in membranes of cultured HEK-293 cells expressing rat mGluR5. The structure-activity relationships showed that electronegative aromatic substituents in the para-position of the benzamide moiety of CDPPB increase potency. Both binding and functional activities were further increased with a halogen atom in the ortho-position of the 1-phenyl ring. These effects of substitution do not match those of either aromatic ring of MPEP [2-methyl-6-(phenylethynyl)-pyridine] for the antagonist allosteric binding site. Combination of the optimal substituents and aromatic positions resulted in 4-nitro-N-(1-(2-fluorophenyl)-3-phenyl-1H-pyrazol-5-yl)benzamide (VU-1545) showing Ki = 156 ± 29 nM and EC50 = 9.6 ± 1.9 nM in the binding and functional assays, respectively.
