185222-90-6Relevant articles and documents
Chiral resolution and stereospecificity of 6-phenyl-4-phenylethynyl- 1,4-dihydropyridines as selective A3 adenosine receptor antagonists
Jiang, Ji-Long,Li, An-Hu,Jang, Soo-Yeon,Chang, Louis,Melman, Neli,Moro, Stefano,Ji, Xiao-Duo,Lobkovsky, Emil B.,Clardy, Jon C.,Jacobson, Kenneth A.
, p. 3055 - 3065 (2007/10/03)
Racemic 6-phenyl-4-phenylethynyl-1,4-dihydropyridine derivatives have been shown to be highly selective A3 adenosine receptor antagonists (Jiang et al. J. Med. Chem. 1997, 40, 2596-2608). Methods for resolving the optical isomers at the C4 position, involving selective crystallization or chromatographic separation of diastereomeric ester derivatives, have been developed. Optically pure glycerol and threitol derivatives were used as chiral auxiliary groups for ester formation at the 3-position, resulting in diastereomeric mixtures of dihydropyridines. Esterification of a 6-phenyl-4- phenylethynyl-1,4-dihydropyridine derivative at the 3-position with a chiral, protected glycerol moiety, (S)-(+)-2,2-dimethyl-1,3-dioxolane-4-methanol, allowed the selective crystallization of a pure diastereomer, 9. The 1H NMR spectrum of 9 using the lanthanide shift reagent Eu(fod)3 indicated optical purity, and the (4S,2'R)-configuration was assigned using X-ray crystallography. The noncrystalline (4R,2'R)-isomer 10 was also isolated and shown to be 3-fold more potent than the (4S,2'R)-isomer in binding to A3 receptors. The 2,2-dimethyl-1,3-dioxolane moiety also served as a protected form of a diol, which showed selective reactivity versus a 5-ethyl ester in basic transesterification reactions. A racemic 5-carboxylic acid derivative could not be resolved through crystallization of diastereomeric salts. Enantiomers of 5-benzyl 3-ethyl 2-methyl-6-phenyl-4-phenylethynyl-1,4- dihydropyridine-3,5-dicarboxylate (2) were obtained via an ester derived from (4R,5R)-(-)-2,3-O-isopropylidene-D-threitol at the 3-position, which was resolved using HPLC, and each diastereomer was subsequently deprotected in acidic conditions. The resulting diols were exchanged for ethyl ester groups by base-catalyzed transesterification. The binding of pure enantiomers of 2 at A3 adenosine receptors indicated a 35-fold stereoselectivity for the (4S)-isomer 21. A receptor docking hypothesis, using a previously derived human A3 receptor model, shows the bulkier of the two ester groups (5-Bn) of 21 oriented toward the exofacial side and the 4-position phenylethynyl group situated between transmembrane helical domain TM6 and TM7.
6-phenyl-1,4-dihydropyridine derivatives as potent and selective A3 adenosine receptor antagonists
Jiang, Ji-Long,Van Rhee, A. Michiel,Melman, Neli,Ji, Xiao-Duo,Jacobson, Kenneth A.
, p. 4667 - 4675 (2007/10/03)
An approach to designing dihydropyridines that bind to adenosine receptors without binding to L-type calcium channels has been described. 1,4- Dihydropyridine derivatives substituted with β-styryl or phenylethynyl groups at the 4-position and aryl groups at the 6-position were synthesized and found to be selective for human A3 receptors. Combinations of methyl, ethyl, and benzyl esters were included at the 3- and 5-positions. Affinity was determined in radioligand binding assays at rat brain A1 and A(2A) receptors using [3H]-(R)-PIA [[3H]-(R)-N6(phenylisopropyl)adenosine] and [3H]CGS 21680 [[3H]-2-[[4-(2-carboxyethyl)phenyl]ethylamino]5'-(N- ethylcarbamoyl)adenosine], respectively. Affinity was determined at cloned human and rat A3 receptors using [125I]AB-MECA [N6-(4-amino-3- iodobenzyl)-5'-(N-methylcarbamoyl)-adenosine]. Structure-activity analysis indicated that substitution of the phenyl ring of the β-styryl group but not of the 6-phenyl substituent was tolerated in A3 receptor selective agents. Replacement of the 6-phenyl ring with a 3-thienyl or 3-furyl group reduced the affinity at A3 receptors by 4- and 9-fold, respectively. A 5-benzyl ester 4-trans-β-styryl derivative, 26, with a K(i) value of 58.3 nM at A3 receptors, was > 1700-fold selective vs either A1 receptors or A(2A) receptors. Shifting the benzyl ester to the 3-position lowered the affinity at A3 receptors 3-fold. A 5-benzyl, 3-ethyl ester 4-phenylethynyl derivative, 28, displayed a K(i) value of 31.4 nM at A3 receptors and 1300- fold selectivity vs A1 receptors. The isomeric 3-benzyl, 5-ethyl diester was >600-fold selective for A3 receptors. Oxidation of 28 to the corresponding pyridine derivative reduced affinity at A3 receptors by 88-fold and slightly increased affinity at A1 receptors.