期刊
JOURNAL OF MEDICINAL CHEMISTRY
卷 54, 期 14, 页码 5205-5220出版社
AMER CHEMICAL SOC
DOI: 10.1021/jm2004738
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资金
- King Pharmaceuticals, Inc., Research & Development, 4000 CentreGreen Way, Suite 300, Cary, North Carolina
A series of 4-allyl/benzyl-7,8-dihydro-8-methyl/ethyl-2-[(substituted)isoxazol/pyrazol-3/5-yl]-1H-imidazo[2,1-i]purin-5(4H)-ones has been synthesized and evaluated in radioligand binding assays to determine their affinities at the human A(1), A(2A), and A(3) adenosine receptors. Efficacy at the hA(2B) AR and antagonism of selected ligands at the hA(3) AR were also assessed through cAMP experiments. All of the synthesized molecules exhibited high affinity at the hA(3) AR (K-i values ranging from 1.46 to 44.8 nM), as well as remarkable selectivity versus A(1), A(2A), and A(2B) AR subtypes. Compound (R)-4-allyl-8-ethyl-7,8-dihydro2-(3-methoxy-1-methyl-1H-pyrazol-5-yl)-1H-imidazo[2,1-i]purin-5(4H)-one (R-33) was found to be the most potent and selective ligand of the series (K-i hA(3) = 1.46 nM, K-i hA(2A)/K-i hA(3) > 3425; IC50 hA(2B)/K-i hA(3) > 3425; K-i hA(1)/K-i hA(3) = 1729). Molecular modeling studies were helpful in rationalizing the available structure-activity relationships along with the selectivity profiles of the new series of ligands.
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