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.
Highlights
Targeting the adenosine A2A receptor (A2AR) has emerged as a promising strategy for the treatment of both Alzheimer’s (AD) and Parkinson’s diseases (PD) [1]
The piperidine moiety of compound 2 creates an additional interaction with Glu169. This putative binding mode suggests that introducing a substituent at the C-7 position of the benzoxazole ring would improve affinity by exploring an unexplored hydrophobic pocket (Fig. 3A & 3C)
We introduced a primary amine at this position instead of the aromatic group in order to interact with Asn253, inducing a different orientation of the benzoxazole ring
Summary
Targeting the adenosine A2A receptor (A2AR) has emerged as a promising strategy for the treatment of both Alzheimer’s (AD) and Parkinson’s diseases (PD) [1]. This receptor, one of the four adenosine receptors with A1, A2B and A3, is coupled to the stimulatory G protein [2]. Many A2A antagonists display high potency, constant drawbacks remain such as poor solubility and synthetic tractability and high toxicity [8, 13,14,15] These drawbacks have limited the development of potential drugs targeting this receptor. Two hits were identified from this study as shown in figure 2 (compound 1 and 2) These ligands display promising pharmacokinetic properties but bind the hA2AR in the micromolar-range. The present work describes the structural investigation of benzoxazole scaffold to improve binding affinity while keeping good pharmacokinetic properties
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