212329-36-7Relevant articles and documents
A3 adenosine receptor antagonists
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, (2008/06/13)
Disclosed are pyridine and dihydropyridine derivatives, pharmaceutical compositions comprising one or more of these derivatives, and a method of selectively blocking an A3adenosine receptor of a mammal by the use of one or more of these derivatives. An example of the pyridine derivative is of the formula (I): wherein R2is ethyl, R3is ethylsulfanyl; R4is ethyl, propyl, or hydroxypropyl; R5is ethyl, propyl, fluoroethyl, or fluoropropyl; and R6is phenyl or fluorophenyl. The derivatives of the present invention can be used for inhibiting binding of ligands to an adenosine receptor. The derivatives also can be used for characterizing an adenosine receptor.
Structure-activity relationships and molecular modeling of 3,5-diacyl- 2,4-dialkylpyridine derivatives as selective A3 adenosine receptor antagonists
Li, An-Hu,Moro, Stefano,Melman, Neli,Ji, Xiao-Duo,Jacobson, Kenneth A.
, p. 3186 - 3201 (2007/10/03)
The structure-activity relationships of 6-phenyl-1,4-dihydropyridine derivatives as selective antagonists at human A3 adenosine receptors have been explored (Jiang et al. J. Med. Chem. 1997, 39, 4667-4675). In the present study, related pyridine derivatives have been synthesized and tested for affinity at adenosine receptors in radioligand binding assays. K(i) values in the nanomolar range were observed for certain 3,5-diacyl-2,4- dialkyl-6-phenylpyridine derivatives in displacement of [125I]AB-MECA (N6-(4-amino-3-iodobenzyl)-5'-N-methylcarbamoyladenosine) at recombinant human A3 adenosine receptors. Selectivity for A3 adenosine receptors was determined vs radioligand binding at rat brain A1 and A(2A) receptors. Structure-activity relationships at various positions of the pyridine ring (the 3- and 5-acyl substituents and the 2- and 4-alkyl substituents) were probed. A 4-phenylethynyl group did not enhance A3 selectivity of pyridine derivatives, as it did for the 4-substituted dihydropyridines. At the 2-and 4-positions ethyl was favored over methyl. Also, unlike the dihydropyridines, a thioester group at the 3-position was favored over an ester for affinity at A3 adenosine receptors, and a 5-position benzyl ester decreased affinity. Small cycloalkyl groups at the 6-position of 4-phenylethynyl-1,4- dihydropyridines were favorable for high affinity at human A3 adenosine receptors, while in the pyridine series a 6-cyclopentyl group decreased affinity. 5-Ethyl 2,4-diethyl-3-(ethylsulfanylcarbonyl)-6-phenylpyridine-5- carboxylate, 38, was highly potent at human A3 receptors, with a K(i) value of 20 nM. A 4-propyl derivative, 39b, was selective and highly potent at both human and rat A3 receptors, with K(i) values of 18.9 and 113 nM, respectively. A 6-(3-chlorophenyl) derivative, 44, displayed a K(i) value of 7.94 nM at human A3 receptors and selectivity of 5200-fold. Molecular modeling, based on the steric and electrostatic alignment (SEAL) method, defined common pharmacophore elements for pyridine and dihydropyridine structures, e.g., the two ester groups and the 6-phenyl group. Moreover, a relationship between affinity and hydrophobicity was found for the pyridines.
