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J Med Chem. 2004 Mar 11;47(6):1434-47.

Design, synthesis, and biological evaluation of new 8-heterocyclic xanthine derivatives as highly potent and selective human A2B adenosine receptor antagonists.

Author information

1
Dipartimento di Scienze Farmaceutiche and Dipartimento di Medicina Clinica e Sperimentale-Sezione di Farmacologia, Università di Ferrara, 44100 Ferrara Italy. pgb@dns.unife.it

Abstract

Here we report the synthesis of 8-heterocycle-substituted xanthines as potent and selective A(2B) adenosine receptor antagonists. The structure-activity relationships (SAR) of the xanthines synthesized in binding to recombinant human A(2B) adenosine receptors (ARs) in HEK-293 cells (HEK-A(2B)) and at other AR subtypes were explored. The synthesized compounds showed A(2B) adenosine receptor affinity in the nanomolar range and good levels of selectivity evaluated in radioligand binding assays at human (h) A(1), A(2A), A(2B), and A(3) ARs. We introduced several heterocycles, such as pyrazole, isoxazole, pyridine, and pyridazine, at the 8-position of the xanthine nucleus and we have also investigated different spacers (substituted acetamide, oxyacetamide, and urea moieties) on the heterocycle introduced. Various groups at the 3- and 4-positions of phenylacetamide moiety were studied. This study allowed us to identify the derivatives 2-(3,4-dimethoxyphenyl)-N-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yl]acetamide (29b, MRE2028F20) [K(i)(hA(2B)) = 38 nM, K(i)(hA(1),hA(2A),hA(3)) >1000 nM], N-benzo[1,3]dioxol-5-yl-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yloxy]acetamide (62b, MRE2029F20) [K(i)(hA(2B)) = 5.5 nM, K(i)(hA(1),hA(2A),hA(3)) > 1000 nM], and N-(3,4-dimethoxyphenyl)-2-[5-(2,6-dioxo-1,3-dipropyl-2,3,6,7-tetrahydro-1H-purin-8-yl)-1-methyl-1H-pyrazol-3-yloxy]acetamide (72b, MRE2030F20) [K(i)(hA(2B) = 12 nM, K(i)(hA(1),hA(2A), hA(3)) > 1000 nM], which showed high affinity at the A(2B) receptor subtype and very good selectivity vs the other ARs. Substitution of the acetamide with an urea moiety afforded bioisosteric xanthines with good affinity and selectivity comparable to the acetamide derivatives. Substitution at the para-position of a 4-benzyloxy group of the phenylacetamido chain enhanced affinity at the A(2B) receptor [compound 30b (K(i)(hA(2B)) = 13 nM) vs compound 21b (K(i)(hA(2B) = 56 nM)] but did not favor selectivity. The derivatives with higher affinity at human A(2B) AR proved to be antagonists, in the cyclic AMP assay, capable of inhibiting the stimulatory effect of NECA (100 nM) with IC(50) values in the nanomolar range, a trend similar to that observed in the binding assay (62b, IC(50) = 38 nM; 72b, IC(50) = 46 nM). In conclusion, the 8-pyrazolo-1,3-dipropyl-1H-purine-2,6-dione derivatives described herein represent a new family of selective antagonists for the adenosine A(2B) receptor.

PMID:
14998332
DOI:
10.1021/jm0309654
[Indexed for MEDLINE]

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