110223-15-9Relevant articles and documents
Pyrazinyl ureas revisited: 1-(3-(Benzyloxy)pyrazin-2-yl)-3-(3,4-dichlorophenyl)urea, a new blocker of Aβ-induced mPTP opening for Alzheimer's disease
Elkamhawy, Ahmed,Park, Jung-eun,Hassan, Ahmed H.E.,Pae, Ae Nim,Lee, Jiyoun,Paik, Sora,Park, Beoung-Geon,Roh, Eun Joo
, p. 268 - 278 (2018)
Herein, we report synthesis and evaluation of new twenty-eight pyrazinyl ureas against β amyloid (Aβ)-induced opening of mitochondrial permeability transition pore (mPTP) using JC-1 assay which measures the change of mitochondrial membrane potential (ΔΨm). The neuroprotective effect of seventeen compounds against Aβ-induced mPTP opening was superior to that of the standard Cyclosporin A (CsA). Among them, 1-(3-(benzyloxy)pyrazin-2-yl)-3-(3,4-dichlorophenyl)urea (5) effectively maintained mitochondrial function and cell viabilities on ATP assay and MTT assay. Also, hERG channel assay presented safe cardiotoxicity profile for compound 5. In addition, using CDocker algorithm, a molecular docking model presented a plausible explanation for the elicited differences in efficiencies of the synthesized compounds to reduce the green to red fluorescence as indication of mPTP closure. Hence, this report presents compound 5 as the most promising pyrazinyl urea-based mPTP blocker up to date.
Synthesis and evaluation of 2-(3-arylureido)pyridines and 2-(3-arylureido)pyrazines as potential modulators of Aβ-induced mitochondrial dysfunction in Alzheimer's disease
Elkamhawy, Ahmed,Park, Jung-eun,Hassan, Ahmed H.E.,Pae, Ae Nim,Lee, Jiyoun,Park, Beoung-Geon,Roh, Eun Joo
, p. 529 - 543 (2018/01/01)
A series of 2-(3-arylureido)pyridines and 2-(3-benzylureido)pyridines were synthesized and evaluated as potential modulators for amyloid beta (Aβ)-induced mitochondrial dysfunction in Alzheimer's disease (AD). The blocking activities of forty one small molecules against Aβ-induced mitochondrial permeability transition pore (mPTP) opening were evaluated by JC-1 assay which measures the change of mitochondrial membrane potential (ΔΨm). The inhibitory activity of twenty five compounds against Aβ-induced mPTP opening was superior to that of the standard cyclosporin A (CsA). Six hit compounds have been identified as likely safe in regards to mitochondrial and cellular safety and subjected to assessment for their protective effect against Aβ-induced deterioration of ATP production and cytotoxicity. Among them, compound 7fb has been identified as a lead compound protecting neuronal cells against 67% of neurocytotoxicity and 43% of suppression of mitochondrial ATP production induced by 5 μM concentrations of Aβ. Using CDocker algorithm, a molecular docking model presented a plausible binding mode for these compounds with cyclophilin D (CypD) receptor as a major component of mPTP. Hence, this report presents compound 7fb as a new nonpeptidyl mPTP blocker which would be promising for further development of Alzheimer's disease (AD) therapeutics.
Urea analogs as neuroprotective agents
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Paragraph 0797; 0798, (2016/10/07)
In the brain the present invention refers to mPTP mitochondrial the selectively inhibit action of the improvement of the function of acting as an a neuro-protective agent central nervous system a using the zero therapeutic or prophylactic treatment of a disorder urea derivatives or a pharmaceutically acceptable salt, manufacturing method of these compounds, and methods of using these compounds is pharmaceutical composition contain as the active ingredient an relates.
Necrosulfonamide inhibits necroptosis by selectively targeting the mixed lineage kinase domain-like protein
Liao, Daohong,Sun, Liming,Liu, Weilong,He, Sudan,Wang, Xiaodong,Lei, Xiaoguang
supporting information, p. 333 - 337 (2014/03/21)
Through high-throughput screening of 200000 compounds and subsequent structure-activity relationship (SAR) studies we identified necrosulfonamide (NSA) as a potent small molecule inhibitor for necroptosis, induced by a combination of TNF-a, Smac mimetic, and z-VAD-fmk (T/S/Z). Applying a forward chemical genetic approach, we utilized an NSA based chemical probe to further reveal that NSA selectively targeted the Mixed Lineage Kinase Domain-like Protein (MLKL) to block the necrosome formation.
IMIDAZO COMPOUNDS AND USES THEREOF
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Page/Page column 43-44, (2008/06/13)
N-substituted imidazopyrazinone compounds such as N-alkylated/aralkylated 7H-imidazo[1,2-a]pyrazin-8-one compounds and related analogs are disclosed. Pharmaceutical compositions and kits containing the N-substituted imidazopyrazinone compounds, as well as therapeutic uses thereof, including treatment of arrhythmia, are also disclosed.
Synthesis of Derivatives of Pyrazinopyridimidin-4-ones
Dennin, F.,Blondeau, D.,Sliwa, H.
, p. 1639 - 1643 (2007/10/02)
3-Alkoxy-2-aminopyrazines have been condensed with ethyl ethoxymethylenemalonate and isopropylidene methoxymethylenemalonate to afford 9-alkoxypyrazinopyrimidin-4-ones substituted in the first case by an ethoxycarbonyl group at 3 position.
Antiulcer Agents. 2. Gastric Antisecretory, Cytoprotective, and Metabolic Properties of Substituted Imidazolpyridines and Analogues
Kaminski, James J.,Hilbert, James M.,Pramanik, B. N.,Solomon, Daniel M.,Conn, David J.,et al.
, p. 2031 - 2046 (2007/10/02)
The search for a successor to 3-(cyanomethyl)-2-methyl-8-(phenylmethoxy)imidazopyridine, Sch 28080 (27), a compound that exhibits gastric antisecretory and cytoprotective properties and has undergone clinical evaluation as an antiulcer agent, has culminated in the identification of four related compounds that exhibit pharmacologic profiles similar to that of 27.In three of these potential successors an amino group functions as a surrogate for the 3-cyanomethyl substituent of the prototype.The present work concerns, in addition to an evaluation of the structure-activity relationships of a series of analogues of 27, preliminary studies of the pharmacodynamics and metabolism of 27, performed with the aid of cyano carbon labeled versions of the drug (13C labeled; 28; 14C labeled, 29).These studies have shown that 27 is well-absorbed and extensively metabolized and that the major metabolite of 27 is the thiocyanate anion.A similar study performed on 3-amino-2-methyl-8-(phenylmethoxy)imidazopyridine, labeled at the 3-position with carbon-13 (41) or carbon-14 (42), revealed that this compound, which has an antisecretory/cytoprotective profile comparable to that of 27, is also metabolized to thiocyanate anion, although this must occur via a different mechanism.The chemistry section includes a discussion of the potential sites of protonation of the pharmacologically similar 3-amino analogue 40 and the structurally related imidazopyrazine 67.Predictions based on charge density and protonation product stabilities are presented.That N1 is the site of protonation in these analogues has been definitively demonstrated by X-ray crystal structure analysis, which alsounequivocally established the assigned imidazopyrazine ring structure.
