15763-11-8Relevant articles and documents
2,5′-disubstituted adenosine derivatives: Evaluation of selectivity and efficacy for the adenosine A1, A2A, and A3 receptor
Van Tilburg, Erica W.,Von Frijtag Drabbe Künzel, Jacobien,De Groote, Miriam,IJzerman, Ad P.
, p. 420 - 429 (2002)
Novel 2,5′-disubstituted adenosine derivatives were synthesized in good overall yields starting from commercially available guanosine. Binding affinities were determined for rat adenosine A1 and A2A receptors and human A3 receptors. Emax values were determined for the stimulation or inhibition of cAMP production in CHO Cells expressing human adenosine A2A (EC50 values as well) or A3 receptors, respectively. The compounds displayed affinities in the nanomolar range for both the adenosine A2A and A3 receptor, without substantial preference for either receptor. The derivatives with a 2-(1-hexynyl) group had the highest affinities for both receptors; compound 4 (2-(1-hexynyl)adenosine) had the highest affinity for the adenosine A2A receptor with a Ki value of 6 nM (A3/A2A selectivity ratio of approximately 3), whereas compound 37 (2-(1-hexynyl)-5′-S-methyl-5′-thioadenosine) had the highest affinity for the adenosine A3 receptor with a Ki value of 15 nM (A2A/A3 selectivity ratio of 4). In general, compounds with a relatively small 5′-S-alkyl-5′-thio substituent (methyl-5′-thio) displayed the highest affinities for both the adenosine A2A and A3 receptor; the larger ones (n- or i-propyl-5′-thio) increased the selectivity for the adenosine A3 receptor. The novel compounds were also evaluated in cAMP assays for their (partial) agonistic behavior. Overall, the disubstituted derivatives behaved as partial agonists for both the adenosine A2A and A3 receptor. The compounds showed somewhat higher intrinsic activities on the adenosine A2A receptor than on the A3 receptor. Compounds 37, 40 and 45, 48, with either a 5′-S-methyl-5′-thio or a 5′-S-i-propyl-5′-thio substituent had the lowest intrinsic activities on the adenosine A2A receptor. For the A3 receptor, compounds 34, 35, 38, 39, and 46, 47, with a 5′-S-ethyl-5′-thio or a 5′-S-n-propyl-5′-thio substituent had the lowest intrinsic activities.
Synthesis and biological evaluation of β-D-pentofuranonucleoside derivatives of 2-azidoadenine and 6-azidopurines
Mathe, Christophe,Lioux, Thierry,Gosselin, Gilles
, p. 605 - 609 (2003)
β-D-pentofuranonucleoside derivatives of 2-azidoadenine and 6-azidopurines have been synthesized. The azido-tetrazolo tautomerism observed on such nucleoside analogues has been studied. The compounds were tested for their activity against HIV and HBV but they did not show significant antiviral effect.
2-Substituted α,β-Methylene-ADP Derivatives: Potent Competitive Ecto-5′-nucleotidase (CD73) Inhibitors with Variable Binding Modes
Bhattarai, Sanjay,Pippel, Jan,Scaletti, Emma,Idris, Riham,Freundlieb, Marianne,Rolshoven, Georg,Renn, Christian,Lee, Sang-Yong,Abdelrahman, Aliaa,Zimmermann, Herbert,El-Tayeb, Ali,Müller, Christa E.,Str?ter, Norbert
supporting information, p. 2941 - 2957 (2020/04/10)
CD73 inhibitors are promising drugs for the (immuno)therapy of cancer. Here, we present the synthesis, structure-activity relationships, and cocrystal structures of novel derivatives of the competitive CD73 inhibitor α,β-methylene-ADP (AOPCP) substituted in the 2-position. Small polar or lipophilic residues increased potency, 2-iodo- and 2-chloro-adenosine-5′-O-[(phosphonomethyl)phosphonic acid] (15, 16) being the most potent inhibitors with Ki values toward human CD73 of 3-6 nM. Subject to the size and nature of the 2-substituent, variable binding modes were observed by X-ray crystallography. Depending on the binding mode, large species differences were found, e.g., 2-piperazinyl-AOPCP (21) was >12-fold less potent against rat CD73 compared to human CD73. This study shows that high CD73 inhibitory potency can be achieved by simply introducing a small substituent into the 2-position of AOPCP without the necessity of additional bulky N6-substituents. Moreover, it provides valuable insights into the binding modes of competitive CD73 inhibitors, representing an excellent basis for drug development.
Preparation method of regadenoson
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Paragraph 0032-0040, (2019/12/02)
The invention discloses a preparation method of regadenoson. The method comprises the following steps that 1, amino-2-chloropurine riboside and hydrazine hydrate react with each other by adopting potassium carbonate as a catalyst to prepare 2-hydrazino adenosine; 2, the 2-hydrazino adenosine and 2-formyl-3-oxo-ethyl propionate react with each other by adopting PEG and water as reaction media to obtain a compound of a formula (3); 3, the compound of the formula (3) and a 25-30% methyl amine water solution react with each other by adopting PEG as a reaction medium to obtain regadenoson. The amino-2-chloropurine riboside is adopted as a starting raw material, by adopting inorganic base potassium carbonate, the selectivity of the first-step reaction is improved, and the consumption of toxic substances hydrazine hydrates is lowered to the minimum. In the synthesis process, polyethylene glycol is adopted as the reaction medium, the reaction needed time is effectively shortened, and the reaction temperature is lowered; meanwhile, the good yield and purity are obtained.
Design, synthesis and biological evaluation of 2-hydrazinyladenosine derivatives as A2A adenosine receptor ligands
Zhang, Min,Fan, Shiyong,Zhou, Xinbo,Xie, Fei,Li, Song,Zhong, Wu
, p. 310 - 324 (2019/07/02)
To obtain potential A2A adenosine receptor agonists, a series of 2-hydrazinyladenosine derivatives were synthesized and assayed for adenosine receptors activity using radioligand binding activity assays. The binding activity of the subtypes was examined, and the structure-activity relationship of this class of compounds at the A2A receptor was investigated. A fragment-based computer-aided design method was used to modify the 2-position side chain structures with different structural fragments, and the newly generated molecules were docked to the A2A receptor to assess scoring and screening activity. To synthesize compounds with better scoring activity, the newly synthesized compounds were tested for in vitro receptor binding activity. 2-Hydrazinyladenosine derivatives of 32 new structural types were designed and synthesized, with the most potent adenosine derivative 23 exhibiting a Ki value of 1.8 nM for A2AAR and significant selectivity for the A2A receptor compared to the A1 receptor. In addition to, compound 23, 24, 30, 31, and 42 also exhibited potent A2A receptor selectivity, with Ki values for the A2A receptor of 6.4, 20, 67 and 6.3 nM, respectively. We also found that compound 35 has a high A1 receptor selectivity, with a Ki value for the A1 receptor of 4.5 nM. Further functional assays also demonstrated that these compounds have potent A2A receptor agonist activity. The study shows the applicability of an in silico fragment-based molecular design for rational lead optimization in A2AAR.
NOVEL POLYMORPH OF REGADENOSON AND PROCESS FOR PREPARATION THEREOF
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Paragraph 0032; 0051, (2018/05/24)
Processes are provided for the preparation of a stable polymorphic form C of regadenoson, the process involving steps of a) obtaining a solution of regadenoson in benzyl alcohol solvent, b) maintaining the reaction mixture of step a) to about 10° C. to about 90° C., and c) isolating the stable polymorphic form C of regadenoson. Polymorphic form C may be characterized by an x-ray powder diffraction pattern with peaks at about 6.1, 10.2, 10.6, 19.0 and 25.4.±0.2 degrees 2-theta.
Modified adenosine receptor agonist nano probe and its preparation and use
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Paragraph 0037; 0038, (2018/08/03)
The invention belongs to the biomedical field, and relates to a modification adenosine receptor agonist nanoprobe, and a production method and a use thereof. The general formula of the nanoprobe is IR783-Den-(PEG-Reg)x, wherein Den is a probe vector fifth-generation polyamidoamine dendrimer; IR783 is a near infrared fluorescent group, and PEG is polyethylene glycol with the molecular weight of 10-40k; and Reg is an adenosine A2A receptor specific agonist Regadenason, and x is the number of PEGReg marked on a probe. In the invention, one end of difunctional polyethylene glycol (Mal-PEG-NHS) is connected with the probe vector Den through a maleimide group, and the other end is connected with the adenosine receptor agonist Reg through an N-hydroxysuccinimidyl group. The quantity of the adenosine receptor agonist modified on the surface of the probe is adjusted by controlling a feeding ratio. The modification adenosine receptor agonist nanoprobe is of great research and clinical significance to improving the brain disease treatment effect, reducing the toxic side effects in the treatment process and promoting the clinic transformation of the individualized treatment schemes of brain diseases.
2-hydrazino adenosine and preparation method thereof
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Paragraph 0038; 0042; 0043, (2017/09/02)
The invention belongs to the field of pharmaceutical chemical engineering and relates to 2-hydrazino adenosine and a preparation method thereof. According to the method disclosed by the invention, a chemical compound shown as a formula II reacts with hydrazine hydrate in the presence or the absence of a polar solvent and the reaction formula is shown as follows. The 2-hydrazino adenosine crystal prepared by adopting the method is high in yield, high in purity and low in cost; the method has the advantages of being friendly to the environment, simple and convenient to operate and easy in industrial scale-up and has a very good industrial application prospect; and the 2-hydrazino adenosine can be used for preparing an adenosine receptor agonist, i.e. regadenoson.
PROCESS OF MAKING REGADENOSON AND NOVEL POLYMORPH THEREOF
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Paragraph 0045; 0046, (2016/09/26)
Novel processes for making the N-pyrrazole substituted 2-adenosine derivative regadenoson and a novel polymorph thereof. The novel polymorph of regadenoson designated form H and drug substances and pharmaceutical compositions including the novel polymorph H are disclosed.
STABLE SOLID FORMS OF REGADENOSON
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Page/Page column 11, (2014/10/29)
A process for the preparation of the amorphous form of Regadenoson of formula (I) is disclosed together with new crystalline polymorphic forms E, F and G and methods for their preparation. Regadenoson amorphous form can be prepared in mild reaction conditions with high chemical purity (>99.6%) and high stability to the heating. A particularly thermodynamically stable anhydrous crystalline form of Regadenoson (form G) is also disclosed, provided with high stability not when exposed to 90% RH at 25°C for 96 hour, but also to the heating up to 200°C.
