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Development of novel oxazolo[5,4- d ]pyrimidines as competitive CB 2 neutral antagonists based on scaffold hopping
journal contribution
posted on 2023-06-09, 11:43 authored by Wei Tuo, Mélanie Bollier, Natascha Leleu-Chavain, Lucas Lemaire, Amélie Barczyk, Xavier Dezitter, Frédérique Klupsch, Fabien Szczepanski, John SpencerJohn Spencer, Philippe Chavatte, Régis MilletA series of novel oxazolo[5,4-d]pyrimidines was designed via a scaffold hopping strategy and synthesized through a newly developed approach. All these compounds were evaluated for their biological activity toward CB1/CB2 cannabinoid receptors, their metabolic stability in mice liver microsomes and their cytotoxicity against several cell lines. Eight compounds have been identified as CB2 ligands with Ki values less than 1?µM. It is noteworthy that 2-(2-chlorophenyl)-5-methyl-7-(4-methylpiperazin-1-yl) oxazolo[5,4-d]pyrimidine 47 and 2-(2-chlorophenyl)-7-(4-ethylpiperazin-1-yl)- 5-methyloxazolo[5,4-d]pyrimidine 48 showed CB2 binding affinity in the nanomolar range and significant selectivity over CB1 receptors. Interestingly, functionality studies imply that they behave as competitive neutral antagonists. Moreover, all tested compounds are devoid of cytotoxicity toward several cell lines, including Chinese hamster ovary cells (CHO) and human colorectal adenocarcinoma cells HT29.
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Publication status
- Published
File Version
- Accepted version
Journal
European Journal of Medicinal ChemistryISSN
0223-5234Publisher
ElsevierExternal DOI
Volume
146Page range
68-78Department affiliated with
- Chemistry Publications
Full text available
- Yes
Peer reviewed?
- Yes
Legacy Posted Date
2018-01-23First Open Access (FOA) Date
2019-01-16First Compliant Deposit (FCD) Date
2018-01-22Usage metrics
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