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Development of novel oxazolo[5,4- d ]pyrimidines as competitive CB 2 neutral antagonists based on scaffold hopping

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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 Millet
A 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.

History

Publication status

  • Published

File Version

  • Accepted version

Journal

European Journal of Medicinal Chemistry

ISSN

0223-5234

Publisher

Elsevier

Volume

146

Page range

68-78

Department affiliated with

  • Chemistry Publications

Full text available

  • Yes

Peer reviewed?

  • Yes

Legacy Posted Date

2018-01-23

First Open Access (FOA) Date

2019-01-16

First Compliant Deposit (FCD) Date

2018-01-22

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