- Preclinical evaluation of 1,2,4-triazole-based compounds targeting voltage-gated sodium channels (VGSCs) as promising anticonvulsant drug candidates
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Epilepsy is a chronic neurological disorder affecting nearly 65–70 million people worldwide. Despite the observed advances in the development of new antiepileptic drugs (AEDs), still about 30–40% of patients cannot achieve a satisfactory seizure control. In our current research, we aimed at using the combined results of radioligand binding experiments, PAMPA-BBB assay and animal experimentations in order to design a group of compounds that exhibit broad spectrum of anticonvulsant activity. The synthesized 4-alkyl-5-substituted-1,2,4-triazole-3-thione derivatives were primarily screened in the maximal electroshock-induced seizure (MES) test in mice. Next, the most promising compounds (17, 22) were investigated in 6 Hz (32 mA) psychomotor seizure model. Protective effect of compound 22 was almost similar to that of levetiracetam. Moreover, these compounds did not induce genotoxic and hemolytic changes in human cells as well as they were characterized by low cellular toxicity. Taking into account the structural requirements for good anticonvulsant activity of 4-alkyl-5-aryl-1,2,4-triazole-3-thiones, it is visible that small electron-withdrawing substituents attached to phenyl ring have beneficial effects both on affinity towards VGSCs and protective activity in the animal models of epilepsy.
- Kaproń, Barbara,?uszczki, Jarogniew J.,Siwek, Agata,Karcz, Tadeusz,Nowak, Gabriel,Zagaja, Miros?aw,Andres-Mach, Marta,Stasi?owicz, Anna,Cielecka-Piontek, Judyta,Kocki, Janusz,Plech, Tomasz
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- Preparation method for triazole compound
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The invention discloses a preparation method for a triazole compound namely N-((5-(3-fluorophenyl)-2H-1,2,4-triazole-3-yl)methyl)-N-propylprop-1-amine. The preparation method prepares a target product7 with 3-(3-fluorophenyl)ethyl acrylate as a starting m
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Paragraph 0024; 0025; 0026
(2018/03/26)
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- 4-alkyloxyimino derivatives of uridine-5′-triphosphate: Distal modification of potent agonists as a strategy for molecular probes of P2Y 2, P2Y4, and P2Y6 receptors
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Extended N4-(3-arylpropyl)oxy derivatives of uridine-5′-triphosphate were synthesized and potently stimulated phospholipase C stimulation in astrocytoma cells expressing G protein-coupled human (h) P2Y receptors (P2YRs) activated by UTP (P2Y2/4R) or UDP (P2Y6R). The potent P2Y4R-selective N4-(3- phenylpropyl)oxy agonist was phenyl ring-substituted or replaced with terminal heterocyclic or naphthyl rings with retention of P2YR potency. This broad tolerance for steric bulk in a distal region was not observed for dinucleoside tetraphosphate agonists with both nucleobases substituted. The potent N 4-(3-(4-methoxyphenyl)-propyl)oxy analogue 19 (EC50: P2Y2R, 47 nM; P2Y4R, 23 nM) was functionalized for chain extension using click tethering of fluorophores as prosthetic groups. The BODIPY 630/650 conjugate 28 (MRS4162) exhibited EC50 values of 70, 66, and 23 nM at the hP2Y2/4/6Rs, respectively, and specifically labeled cells expressing the P2Y6R. Thus, an extended N4-(3- arylpropyl)oxy group accessed a structurally permissive region on three G q-coupled P2YRs, and potency and selectivity were modulated by distal structural changes. This freedom of substitution was utilized to design of a pan-agonist fluorescent probe of a subset of uracil nucleotide-activated hP2YRs.
- Jayasekara, P. Suresh,Barrett, Matthew O.,Ball, Christopher B.,Brown, Kyle A.,Hammes, Eva,Balasubramanian, Ramachandran,Harden, T. Kendall,Jacobson, Kenneth A.
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p. 3874 - 3883
(2014/05/20)
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- 7-HYDROXY-PYRAZOLO[1,5-A] PYRIMIDINE COMPOUNDS AND THEIR USE AS CCR2 RECEPTOR ANTAGONISTS
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The compounds of formula (I) are antagonists of the CCR2 receptor Wherein R1-7 and A are as defined in the claims.
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Paragraph 0252
(2013/10/07)
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- 7-HYDROXY-PYRAZOLO[1,5-A] PYRIMIDINE COMPOUNDS AND THEIR USE AS CCR2 RECEPTOR ANTAGONISTS
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The compounds of formula (I) are antagonists of the CCR2 receptor Wherein R1-7 and A are as defined in the claims.
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Page/Page column 39
(2012/04/17)
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- 3-arylpropanoate esters through the palladium-catalyzed reaction of aryl halides with acrolein diethyl acetal
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The reaction of aryl halides with acrolein diethyl acetal in the presence of Pd(OAc)2, n-Bu3N, and n-Bu4NCl in DMF at 90°C affords ethyl 3-arylpropanoates. A variety of functional groups are tolerated in the aryl halides, including ether, aldehyde, ketone, ester, nitrile, and nitro groups. ortho-Substituents do not hamper the reaction. 3-Arylpropanoate esters were isolated in good to excellent yields with many neutral, electron-rich and electron-poor aryl iodides and electron-poor aryl bromide. Neutral and electron-rich aryl bromides gave the desired ester in moderate yields.
- Battistuzzi, Gianfranco,Cacchi, Sandro,Fabrizi, Giancarlo,Bernini, Roberta
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p. 1133 - 1136
(2007/10/03)
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- Inhibition of uridine phosphorylase: Synthesis and structure-activity relationships of aryl-substituted 5-benzyluracils and 1-[(2- hydroxyethoxy)methyl]-5-benzyluracils
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A series of 1-[(2-hydroxyethoxy)methyl]-5-benzyluracils were synthesized and tested for inhibition of murine liver uridine phosphorylase (UrdPase). Inhibitors of UrdPase are reported to enhance the chemotherapeutic utility of 5-fluoro-2'-deoxyuridine and 5-fluorouracil and to ameliorate zidovudine- induced anemia in animal models. We prepared a series of 5-aryl-substituted analogues of 5-benzylacyclouridine (BAU), a good inhibitor of UrdPase (IC50 of 0.46 μM), to develop a compound with enhanced potency and improved pharmacokinetics. The first phase of structure-activity relationship studies on a series of 32 aryl-substituted 5-benzyluracils found several 5-(3- alkoxybenzyl) analogues of 5-benzyluracil with enhanced potency. The acyclovir side chain, the (2-hydroxyethoxy)methyl group, was substituted on the more potent aryl-substituted 5-benzyluracils. The two most potent compounds, 10y (3-propoxy) and 10dd (3-sec-butoxy), were inhibitors of UrdPase with IC50s of 0.047 and 0.027 μM, respectively. Six compounds were tested in vivo for effects on steady-state concentrations of circulating uridine in rats. Plasma uridine levels were elevated 3-9-fold by compound levels that ranged from 8 to 50 μM.
- Orr,Musso,Boswell,Kelley,Joyner,Davis,Baccanari
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p. 3850 - 3856
(2007/10/02)
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