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.
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
, 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.
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.
