Antagonists of the adenosine A 2A receptor based on a 2-arylbenzoxazole scaffold: Investigation of the C5- and C7-positions to enhance affinity - Archive ouverte HAL
Journal Articles European Journal of Medicinal Chemistry Year : 2018

Antagonists of the adenosine A 2A receptor based on a 2-arylbenzoxazole scaffold: Investigation of the C5- and C7-positions to enhance affinity

Abstract

We have recently reported a series of 2-furoyl-benzoxazoles as potential A2A adenosine receptor (A2AR) antagonists. Two hits were identified with interesting pharmacokinetic properties but were find to bind the hA2AR receptor in the micromolar-range. Herein, in order to enhance affinity toward the hA2AR, we explored the C5- and C7-position of hits 1 and 2 based on docking studies. These modifications led to compounds with nanomolar-range affinity (e.g. 6a, Ki = 40 nM) and high antagonist activity (e.g. 6a, IC50 = 70.6 nM). Selected compounds also exhibited interesting in vitro DMPK (Drug Metabolism and Pharmacokinetics) properties including high solubility and low cytotoxicity. Therefore, the benzoxazole ring appears as a highly effective scaffold for the design of new A2A antagonists.
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hal-02060715 , version 1 (08-03-2019)

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Romain Duroux, Laurence Agouridas, Nicolas Renault, Jamal El Bakali, Christophe Furman, et al.. Antagonists of the adenosine A 2A receptor based on a 2-arylbenzoxazole scaffold: Investigation of the C5- and C7-positions to enhance affinity. European Journal of Medicinal Chemistry, 2018, 144, pp.151-163. ⟨10.1016/j.ejmech.2017.12.007⟩. ⟨hal-02060715⟩
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