Optimization of arylindenopyrimidines as potent adenosine A2A/A1 antagonists

doi:10.1016/j.bmcl.2010.03.024

Bioorganic & Medicinal Chemistry Letters

Volume 20, Issue 9, 1 May 2010, Pages 2868-2871

https://doi.org/10.1016/j.bmcl.2010.03.024 Get rights and content

Abstract

Two reactive metabolites were identified in vivo for the dual A_2A/A₁ receptor antagonist 1. Two strategies were implemented to successfully mitigate the metabolic liabilities associated with 1. Optimization of the arylindenopyrimidines led to a number of amide, ether, and amino analogs having comparable in vitro and in vivo activity.

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A novel series of carbamate substituted 2-amino-4,6-diphenylpyrimidines was evaluated as potential dual adenosine A₁ and A_2A receptor antagonists. The majority of the synthesised compounds exhibited promising dual affinities, with A₁K_i values ranging from 0.175 to 10.7 nM and A_2AK_i values ranging from 1.58 to 451 nM. The in vivo activity illustrated for 3-(2-amino-6-phenylpyrimidin-4-yl)phenyl morpholine-4-carboxylate (4c) is indicative of the potential of these compounds as therapeutic agents in the treatment of Parkinson’s disease, although physicochemical properties may require optimisation.
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Citation Excerpt :
Based on the aforementioned findings, the aim of the present study was to explore the necessity of the methylene bridge as present in the indenopyrimidine or indenopyrimidone scaffolds previously synthesised [40–42,46] and to further investigate the structure–activity relationships of the 2-aminopyrimidine scaffold for dual antagonism of adenosine A1 and A2A receptors. We thus set out to synthesise firstly, a set of 2-aminopyrimidines substituted with simple electron withdrawing and donating groups (8a – h), and secondly an amide substituted series (8j – n), related to the indenopyrimidones (e.g. 5) as synthesised by Shook and co-workers [41]. We report herein their affinities for adenosine A2A and A1 receptors, the results of docking selected compounds into the adenosine A2A receptor's binding site, as well as the in vivo activities of selected compounds.
In this study thirteen 2-aminopyrimidine derivatives were synthesised and screened as potential antagonists of adenosine A₁ and A_2A receptors in order to further investigate the structure activity relationships of this class of compounds. 4-(5-Methylfuran-2-yl)-6-[3-(piperidine-1-carbonyl)phenyl]pyrimidin-2-amine (8m) was identified as a compound with high affinities for both receptors, with an A_2AKi value of 6.34 nM and an A₁Ki value of 9.54 nM. The effect of selected compounds on the viability of cultured cells was assessed and preliminary results indicate low cytotoxicity. In vivo efficacy at A_2A receptors was illustrated for compounds 8k and 8m since these compounds attenuated haloperidol-induced catalepsy in rats. A molecular docking study revealed that the interactions between the synthesised compounds and the adenosine A_2A binding site most likely involve Phe168 and Asn253, interactions which are similar for structurally related adenosine A_2A receptor antagonists.
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Optimization of arylindenopyrimidines as potent adenosine A2A/A1 antagonists

Abstract

Graphical abstract

Purinergic Signal.

Curr. Pharm. Des.

Neuropharmacology

Synth. Commun.

Psychopharamcology

Trends Neurosci.

Synthesis

Pharmacol. Rev.

Curr. Top. Med. Chem.

Optimization of arylindenopyrimidines as potent adenosine A_2A/A₁ antagonists