Discovery of simplified N²-substituted pyrazolo[3,4-d]pyrimidine derivatives as novel adenosine receptor antagonists : efficient synthetic approaches, biological evaluations and molecular docking studies
Copyright © 2014 Elsevier Ltd. All rights reserved..
In the present study, a molecular simplification approach was employed to design novel bicyclic pyrazolo[3,4-d]pyrimidine (PP) derivatives from tricyclic pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines (PTP) as promising human A3 adenosine receptor (hA3AR) antagonists. All the target compounds were synthesized using novel and efficient synthetic schemes and the structure-activity relationship studies of these PPs were explored through the synthesis of a series of PTP analogues with various substituents. Substituents with different lipophilicity and steric hindrance (e.g., alkyl and aryl-alkyl) functions were introduced at N(2) position of the pyrazole ring, while acyl groups with different electronic properties were introduced at C(6) position of the bicyclic nucleus to probe both electronic and positional effects. Most of the synthesized derivatives of the PP series presented good affinity at the hA3AR, as indicated by the low micromolar range of Ki values and among them, compound 63 with N(2) neopentyl substituents showed most potent hA3AR affinity with Ki value of 0.9 μM and high selectivity (hA1AR/hA3AR=>111 & hA2AAR/hA3AR=>111) towards other adenosine receptor subtypes. Interestingly, small isopropyl groups at N(2) position displayed high affinity at another receptor subtype (hA2AAR, e.g., compound 55, with Ki hA2AAR=0.8 μM), while they were less favorable at the hA3AR. Molecular docking analysis was also performed to predict the possible binding mode of target compounds inside the hA3AR and hA2AAR. Overall, PP derivatives represent promising starting points for new AR antagonists.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2014 |
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| Erschienen: |
2014 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:22 |
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| Enthalten in: |
Bioorganic & medicinal chemistry - 22(2014), 5 vom: 01. März, Seite 1751-65 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Venkatesan, Gopalakrishnan [VerfasserIn] |
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| Links: |
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| Anmerkungen: |
Date Completed 08.12.2014 Date Revised 24.02.2014 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1016/j.bmc.2014.01.018 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 100 | 1 | |a Venkatesan, Gopalakrishnan |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Discovery of simplified N²-substituted pyrazolo[3,4-d]pyrimidine derivatives as novel adenosine receptor antagonists |b efficient synthetic approaches, biological evaluations and molecular docking studies |
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| 520 | |a Copyright © 2014 Elsevier Ltd. All rights reserved. | ||
| 520 | |a In the present study, a molecular simplification approach was employed to design novel bicyclic pyrazolo[3,4-d]pyrimidine (PP) derivatives from tricyclic pyrazolo[4,3-e]-1,2,4-triazolo-[1,5-c]pyrimidines (PTP) as promising human A3 adenosine receptor (hA3AR) antagonists. All the target compounds were synthesized using novel and efficient synthetic schemes and the structure-activity relationship studies of these PPs were explored through the synthesis of a series of PTP analogues with various substituents. Substituents with different lipophilicity and steric hindrance (e.g., alkyl and aryl-alkyl) functions were introduced at N(2) position of the pyrazole ring, while acyl groups with different electronic properties were introduced at C(6) position of the bicyclic nucleus to probe both electronic and positional effects. Most of the synthesized derivatives of the PP series presented good affinity at the hA3AR, as indicated by the low micromolar range of Ki values and among them, compound 63 with N(2) neopentyl substituents showed most potent hA3AR affinity with Ki value of 0.9 μM and high selectivity (hA1AR/hA3AR=>111 & hA2AAR/hA3AR=>111) towards other adenosine receptor subtypes. Interestingly, small isopropyl groups at N(2) position displayed high affinity at another receptor subtype (hA2AAR, e.g., compound 55, with Ki hA2AAR=0.8 μM), while they were less favorable at the hA3AR. Molecular docking analysis was also performed to predict the possible binding mode of target compounds inside the hA3AR and hA2AAR. Overall, PP derivatives represent promising starting points for new AR antagonists | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a Research Support, Non-U.S. Gov't | |
| 650 | 4 | |a Adenosine receptor antagonist | |
| 650 | 4 | |a Homology modeling | |
| 650 | 4 | |a Molecular docking | |
| 650 | 4 | |a Pyrazolo[3,4-d]pyrimidine | |
| 650 | 4 | |a Structure affinity relationship | |
| 650 | 7 | |a Purinergic P1 Receptor Antagonists |2 NLM | |
| 700 | 1 | |a Paira, Priyankar |e verfasserin |4 aut | |
| 700 | 1 | |a Cheong, Siew Lee |e verfasserin |4 aut | |
| 700 | 1 | |a Vamsikrishna, Kosaraju |e verfasserin |4 aut | |
| 700 | 1 | |a Federico, Stephanie |e verfasserin |4 aut | |
| 700 | 1 | |a Klotz, Karl-Norbert |e verfasserin |4 aut | |
| 700 | 1 | |a Spalluto, Giampiero |e verfasserin |4 aut | |
| 700 | 1 | |a Pastorin, Giorgia |e verfasserin |4 aut | |
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