The synthesis of 8-heterocycle-substituted xanthines as potent and selective A2B adenosine receptor antagonists was reported. The structure-activity relationships (SAR) of the xanthines synthesized in binding to recombinant human A2B adenosine receptors (ARs) in HEK-293 cells (HEK-A2B) and at other AR subtypes were explored. The synthesized compds. showed A2B adenosine receptor affinity in the nanomolar range and good levels of selectivity evaluated in radioligand binding assays at human (h) A1, A2A, A2B, and A3 ARs. Several heterocycles, such as pyrazole, isoxazole, pyridine, and pyridazine, were introduced at the 8-position of the xanthine nucleus and different spacers (substituted acetamide, oxyacetamide, and urea moieties) were investigated. Various groups at the 3- and 4-positions of phenylacetamide moiety were studied. This study allowed us to identify 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 (MRE2028F20) [Ki(hA2B) = 38 nM, Ki(hA1,hA2A,hA3) >1000 nM], N-1,3-benzodioxol-5-yl-2-[[1-methyl-5-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-1H-pyrazol-3-yl]oxy]acetamide (I, MRE2029F20) [Ki(hA2B) = 5.5 nM, Ki(hA1,hA2A,hA3) > 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 (MRE2030F20) [Ki(hA2B) = 12 nM, Ki(hA1,hA2A, hA3) > 1000 nM], which showed high affinity at the A2B 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 derivs. Substitution at the para-position of a 4-benzyloxy group of the phenylacetamido chain enhanced affinity at the A2B receptor but did not favor selectivity. The derivs. with higher affinity at human A2B AR proved to be antagonists, in the cAMP assay, capable of inhibiting the stimulatory effect of NECA (100 nM) with IC50 values in the nanomolar range, a trend similar to that obsd. in the binding assay for I (IC50 = 38 nM) for MRE2029F20 (IC50 = 46 nM). In conclusion, the 8-pyrazolo-1,3-dipropyl-1H-purine-2,6-dione derivs. described herein represent a new family of selective antagonists for the adenosine A2B receptor.
Design, synthesis, and biological evaluation of new 8-heterocyclic xanthine derivatives as highly potent and selective human A(2B) adenosine receptor antagonists
BARALDI, Pier Giovanni;AGHAZADEH TABRIZI, Mojgan;PRETI, Delia;BOVERO, Andrea;ROMAGNOLI, Romeo;FRUTTAROLO, Francesca;VARANI, Katia;GESSI, Stefania;MERIGHI, Stefania;BOREA, Pier Andrea
2004
Abstract
The synthesis of 8-heterocycle-substituted xanthines as potent and selective A2B adenosine receptor antagonists was reported. The structure-activity relationships (SAR) of the xanthines synthesized in binding to recombinant human A2B adenosine receptors (ARs) in HEK-293 cells (HEK-A2B) and at other AR subtypes were explored. The synthesized compds. showed A2B adenosine receptor affinity in the nanomolar range and good levels of selectivity evaluated in radioligand binding assays at human (h) A1, A2A, A2B, and A3 ARs. Several heterocycles, such as pyrazole, isoxazole, pyridine, and pyridazine, were introduced at the 8-position of the xanthine nucleus and different spacers (substituted acetamide, oxyacetamide, and urea moieties) were investigated. Various groups at the 3- and 4-positions of phenylacetamide moiety were studied. This study allowed us to identify 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 (MRE2028F20) [Ki(hA2B) = 38 nM, Ki(hA1,hA2A,hA3) >1000 nM], N-1,3-benzodioxol-5-yl-2-[[1-methyl-5-(2,3,6,7-tetrahydro-2,6-dioxo-1,3-dipropyl-1H-purin-8-yl)-1H-pyrazol-3-yl]oxy]acetamide (I, MRE2029F20) [Ki(hA2B) = 5.5 nM, Ki(hA1,hA2A,hA3) > 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 (MRE2030F20) [Ki(hA2B) = 12 nM, Ki(hA1,hA2A, hA3) > 1000 nM], which showed high affinity at the A2B 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 derivs. Substitution at the para-position of a 4-benzyloxy group of the phenylacetamido chain enhanced affinity at the A2B receptor but did not favor selectivity. The derivs. with higher affinity at human A2B AR proved to be antagonists, in the cAMP assay, capable of inhibiting the stimulatory effect of NECA (100 nM) with IC50 values in the nanomolar range, a trend similar to that obsd. in the binding assay for I (IC50 = 38 nM) for MRE2029F20 (IC50 = 46 nM). In conclusion, the 8-pyrazolo-1,3-dipropyl-1H-purine-2,6-dione derivs. described herein represent a new family of selective antagonists for the adenosine A2B receptor.I documenti in SFERA sono protetti da copyright e tutti i diritti sono riservati, salvo diversa indicazione.
