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

Tuo, Wei, Bollier, Mélanie, Leleu-Chavain, Natascha, Lemaire, Lucas, Barczyk, Amélie, Dezitter, Xavier, Klupsch, Frédérique, Szczepanski, Fabien, Spencer, John, Chavatte, Philippe and Millet, Régis (2018) Development of novel oxazolo[5,4- d ]pyrimidines as competitive CB 2 neutral antagonists based on scaffold hopping. European Journal of Medicinal Chemistry, 146. pp. 68-78. ISSN 0223-5234

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Abstract

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.

Item Type: Article
Schools and Departments: School of Life Sciences > Chemistry
Subjects: Q Science
Q Science > QD Chemistry
Q Science > QD Chemistry > QD0241 Organic chemistry
Q Science > QD Chemistry > QD0241 Organic chemistry > QD0415 Biochemistry
Depositing User: John Spencer
Date Deposited: 23 Jan 2018 10:11
Last Modified: 26 Feb 2018 12:40
URI: http://sro.sussex.ac.uk/id/eprint/73070

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