- Design and evaluation of xanthine based adenosine receptor antagonists: Potential hypoxia targeted immunotherapies
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Molecular modeling techniques were applied to the design, synthesis and optimization of a new series of xanthine based adenosine A2A receptor antagonists. The optimized lead compound was converted to a PEG derivative and a functional in vitro bioassay used to confirm efficacy. Additionally, the PEGylated version showed enhanced aqueous solubility and was inert to photoisomerization, a known limitation of existing antagonists of this class.
- Thomas, Rhiannon,Lee, Joslynn,Chevalier, Vincent,Sadler, Sara,Selesniemi, Kaisa,Hatfield, Stephen,Sitkovsky, Michail,Ondrechen, Mary Jo,Jones, Graham B.
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Read Online
- Separation and identification of an impurity from the istradefylline intermediate
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Istradefylline is a selective adenosine antagonist for the A2a receptor, and it is used to treat the Parkinson's disease and improve dyskinesia in the early stage of the Parkinson's disease. An impurity in the istradefylline intermediate A1 (6-amino-1,3-diethyl-2,4-(1H,3H)-pyrimidinedione) was identified by high performance liquid chromatography (HPLC); it was separated by preparative HPLC and further characterized by UV, IR, MS, NMR, 2D NMR and single-crystal XRD analyses. The impurity was identified as (E)-N-ethyl-2-cyano-3-ethylamino-2-butenamide, which originated from the synthetic process of the intermediate A1. The structure of this impurity might affect the efficiency and safety of istradefylline; therefore, the research and control of this impurity are necessary for ensuring the quality of istradefylline.
- Meng, Zihui,Wang, Hongyi,Wang, Yiyun,Xu, Haojie,Xu, Zhibin,Xue, Min,Zheng, Zhonghui
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p. 14493 - 14499
(2020/04/27)
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- Novel, Dual Target-Directed Annelated Xanthine Derivatives Acting on Adenosine Receptors and Monoamine Oxidase B
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Annelated purinedione derivatives have been shown to act as possible multiple-target ligands, addressing adenosine receptors and monoaminooxidases. In this study, based on our previous results, novel annelated pyrimido- and diazepino[2,1-f]purinedione derivatives were designed as dual-target-directed ligands combining A2A adenosine receptor (AR) antagonistic activity with blocking monoamine oxidase B. A library of 19 novel compounds was synthesized and biologically evaluated in radioligand binding studies at AR subtypes and for their ability to inhibit MAO-B. This allowed 9-(2-chloro-6-fluorobenzyl)-3-ethyl-1-methyl-6,7,8,9-tetrahydropyrimido[2,1-f]purine-2,4(1H,3H)-dione (13 e; Ki human A2AAR: 264 nM and IC50 human MAO-B: 243 nM) to be identified as the most potent dual-acting ligand from this series. ADMET parameters were estimated in vitro, and analysis of the structure-activity relationships was complemented by molecular-docking studies based on previously published X-ray structures of the protein targets. Such dual-acting ligands, by selectively blocking A2A AR, accompanied by the inhibition of dopamine metabolizing enzyme MAO-B, might provide symptomatic and neuroprotective effects in, among others, the treatment of Parkinson disease.
- Brockmann, Andreas,Doroz-P?onka, Agata,Ja?ko, Piotr,Kie?-Kononowicz, Katarzyna,Kuder, Kamil J.,Latacz, Gniewomir,Müller, Christa E.,Olejarz-Maciej, Agnieszka,Schabikowski, Jakub,Za?uski, Micha?
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- Synthesis method of 1,3-diethyl-3,7-dihydropurine-2,6-diketone
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The invention relates to a synthesis method of 1,3-diethyl-3,7-dihydropurine-2,6-diketone. The method provided by the invention can solve the technical problems that by the existing synthesis method, sodium hydrosulfite powder is used for reducing to cause unstable yield and high environmental pollution as well as an expensive metal catalyst is used to cause that the raw material cost is high and noble metal recovery is difficult to control. The synthesis method provided by the invention comprises the following steps: performing cyclization reaction under the participation of 1,3-diethyl urea and cyanoacetic acid to obtain 6-amido-1,3-diethyl-1H-pyrimidine-2,4-diketone; performing electrophilic addition reaction on the 6-amido-1,3-diethyl-1H-pyrimidine-2,4-diketone and sodium nitrite under the condition of organic acid to obtain 6-amido-1,3-diethyl-5-nitroso-1H-pyrimidine-2,4-diketone; performing reduction and acylation reaction under the action of zinc powder and formic acid to obtain N-(6-amido-1,2,4-diethyl-1,2,3,4-tetrahydropyrimidine-5-yl)-formamide; performing ring closing under the condition of strong alkali, and performing acidification to obtain the 1,3-diethyl-3,7-pyrimidine-2,6-diketone. The compound is an important medicine compound early-stage raw material and intermediate in the field of research on various new medicines.
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Paragraph 0009; 0011
(2017/10/26)
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- Inhibitory Effects of New Mercapto Xanthine Derivatives in Human mcf7 and k562 Cancer Cell Lines
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A series of new 2-methyl-2-[(1,3-Diethyl-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-yl)thio]-N- substituted arylacetamides were synthesized. The antitumor activity of these purine based compounds were evaluated on breast cancer (MCF7) and leukemic cancer (K562) cell lines via cell viability assay utilizing the tetrazolium dye 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT). These results were substantiated using computer docking experiments (LigandFit docking engine and PMF scoring function) which predict that the antitumor activity of these new compounds may be attributable to their abilities to effectively bind and block oncogenic tyrosine kinases, particularly bcr/abl.
- Sultani, Haider N.,Ghazal, Rasha A.,Hayallah, Alaa M.,Abdulrahman, Loay K.,Abu-Hammour, Khaled,AbuHammad, Shatha,Taha, Mutasem O.,Zihlif, Malek A.
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supporting information
p. 450 - 456
(2017/02/03)
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- Preparation method and use of istradefylline
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The invention relates to the technical field of pharmaceutical chemistry, and particularly relates to a preparation method and use of istradefylline; specifically, with 1,3-diethyl formamide and cyanoacetic acid as raw materials, istradefylline is prepared through cyclization, nitration, reduction, condensation, cyclization, methylation reaction and other steps; the preparation method provided by the invention is simple, high in production efficiency and wide in application prospect.
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Paragraph 0023; 0030; 0037
(2017/08/28)
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- Novel adenosine A2A receptor ligands: A synthetic, functional and computational investigation of selected literature adenosine A2A receptor antagonists for extending into extracellular space
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Growing evidence has suggested a role in targeting the adenosine A 2A receptor for the treatment of Parkinson's disease. The literature compounds KW 6002 (2) and ZM 241385 (5) were used as a starting point from which a series of novel ligands targeting the adenosine A2A receptor were synthesized and tested in a recombinant human adenosine A2A receptor functional assay. In order to further explore these molecules, we investigated the biological effects of assorted linkers attached to different positions on selected adenosine A2A receptor antagonists, and assessed their potential binding modes using molecular docking studies. The results suggest that linking from the phenolic oxygen of selected adenosine A2A receptor antagonists is relatively well tolerated due to the extension towards extracellular space, and leads to the potential of attaching further functionality from this position.
- J?rg, Manuela,Shonberg, Jeremy,Mak, Frankie S.,Miller, Neil D.,Yuriev, Elizabeth,Scammells, Peter J.,Capuano, Ben
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supporting information
p. 3427 - 3433
(2013/06/26)
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- 8-TRIAZOLYLXANTHINE DERIVATIVES, PROCESSES FOR THEIR PRODUCTION AND THEIR USE AS ADENOSINE RECEPTOR ANTAGONISTS
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The invention relates to derivatives of the general formulae (I) and (II) to processes for the production thereof, to pharmaceutical preparations containing said compounds and/or physiologically compatible salts or solvates or prodrugs which can be produced therefrom as well as to the pharmaceutical use of said compounds, the salts or solvates thereof as adenosine receptor antagonists, in particular for the treatment of neurodegenerative disorders, e.g. stroke, amylotrophic lateral sclerosis, dementia, Alzheimer's disease, Parkinson's disease, ischemia/reperfusion injury, inflammation, and/or neurological disorder. The blockade of adenosine receptors could also be useful for other indications regarding the metabolism, e.g. diabetic retinopathy, diabetes mellitus, hyperbaric oxygen - induced retinopathy and/or obesity. Applications could also be the treatment of allergic diseases and autoimmune diseases, including mast cell degranulation, asthma, bronchoconstriction, pulmonary fibrosis, inflammatory or obstructive airways disease and/or chronic obstructive pulmonary disease (COPD). In addition, they could be used to treat cancer. The diseases associated with adenosine receptors are also diabetes, diarrhea, inflammatory bowel disease and/or gastrointestinal tract disorders. Adenosine receptor antagonists could be effective for treating a hepatic disease or condition for reducing fat deposition in the liver or fibrosis of the liver. The use of compounds of general formulae I or II can be associated with many applications e.g., scleroderm arthritis, atherosclerosis, urticaria, myocardial infarction, myocardial reperfusion after ischemia, vasodilation, hypertension, hypersensitivity, myocardial ischemia, heart attack and/or retinopathy of prematurity.
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Page/Page column 28
(2012/06/30)
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- HETEROCYCLIC COMPOUNDS AND USES THEREOF IN THE TREATMENT OF SEXUAL DISORDERS
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Novel heterocyclic compounds, which exhibit a dopamine receptor (preferably a D4 receptor) agonistic activity, and/or a PDE5 inhibitory activity, processes of preparing same, pharmaceutical compositions containing same and uses thereof in the treatment of sexual disorders such as decreased libido, orgasm disorder and erectile dysfunction are disclosed.
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Page/Page column 66-67
(2008/06/13)
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- Novel 1,3-disubstituted 8-(1-benzyl-1H-pyrazol-4-yl) xanthines: High affinity and selective A2B adenosine receptor antagonists
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Adenosine has been suggested to induce bronchial hyperresponsiveness in asthmatics, which is believed to be an A2B adenosine receptor (AdoR) mediated pathway. We hypothesize that a selective, high-affinity A2B AdoR antagonist may provide therapeutic benefit in the treatment of asthma. In an attempt to identify a high-affinity, selective antagonist for the A 2B AdoR, we synthesized 8-(C-4-pyrazolyl) xanthines. Compound 22, 8-(1H-pyrazol-4-yl)-1,3-dipropyl xanthine, is a N-1 unsubstituted pyrazole derivative that has favorable binding affinity (Ki = 9 nM) for the A2B AdoR, but it is only 2-fold selective versus the A1 AdoR. Introduction of a benzyl group at the N-1-pyrazole position of 22 resulted in 19, which had moderate selectivity. The initial focus of the SAR study was on the preparation of substituted benzyl derivatives of 19 because the corresponding phenyl, phenethyl, and phenpropyl derivatives showed a decrease in A2B AdoR affinity and selectivity relative to 19. The preferred substitution on the phenyl ring of 19 contains an electron-withdrawing group, specifically F or CF3 at the m-position, as in 33 and 36 respectively, increases the selectivity while retaining the affinity for the A2B AdoR. Exploring disubstitutions on the phenyl ring of derivatives 33 and 36 led to the 2-chloro-5-trifluoromethylphenyl derivative 50, which retained the A2B AdoR affinity but enhanced the selectivity relative to 36. After optimization of the substitution on the 8-pyrazole xanthine, 1,3-disubstitution of the xanthine core was explored with methyl, ethyl, butyl, and isobutyl groups. In comparison to the corresponding dipropyl analogues, the smaller 1,3-dialkyl groups (methyl and ethyl) increased the A2B AdoR binding selectivity of the xanthine derivatives while retaining the affinity. However, the larger 1,3-dialkyl groups (isobutyl and butyl) resulted in a decrease in both A2B AdoR affinity and selectivity. This final SAR optimization led to the discovery of 1,3-dimethyl derivative 60, 8-(1-(3-(trifluoromethyl) benzyl)-1H-pyrazol-4-yl)-1,3-dimethyl xanthine, a high-affinity (Ki = 1 nM) A2B AdoR antagonist with high selectivity (990-, 690-, and 1000-) for the human A1, A2A, and A3 AdoRs.
- Kalla, Rao V.,Elzein, Elfatih,Perry, Thao,Li, Xiaofen,Palle, Venkata,Varkhedkar, Vaibhav,Gimbel, Arthur,Maa, Tennig,Zeng, Dewan,Zablocki, Jeff
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p. 3682 - 3692
(2007/10/03)
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- An expedient method for the synthesis of 6-substituted uracils under microwave irradiation in a solvent-free medium
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Condensation of malonic acid 1 and ureas 2a-f proceeds smoothly in the presence of acetic anhydride 3 under microwave irradiation in solvent-free conditions to give 6-hydroxy-uracils 4 in excellent yields. Under identical conditions, the condensation of cyanoacetic acid 5 and ureas 2a,b,g and h in the presence of acetic anhydride 3, followed by cyclization in the presence of sodium hydroxide affords 6-amino-uracils 6 in high yields. The work-up procedures are simple and products need no purification.
- Devi, Ipsita,Bhuyan, Pulak J.
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p. 5727 - 5729
(2007/10/03)
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