ABSTRACT
X-ray crystal structural determination of FABP4 in complex with four inhibitors revealed the complex binding modes, and the resulting observations led to improvement of the inhibitory potency of FABP4 inhibitors. However, the detailed structure-activity relationship (SAR) could not be explained from these structural observations. For a more detailed understanding of the interactions between FABP4 and inhibitors, fragment molecular orbital analyses were performed. These analyses revealed that the total interfragment interaction energies of FABP4 and each inhibitor correlated with the ranking of the K i value for the four inhibitors. Furthermore, interactions between each inhibitor and amino acid residues in FABP4 were identified. The oxygen atom of Lys58 in FABP4 was found to be very important for strong interactions with FABP4. These results might provide useful information for the development of novel potent FABP4 inhibitors.
ABSTRACT
A structure-activity relationship study of 6-unsubstituted-1,4-dihydropyridine and 2,6-unsubstituted-1,4-dihydropyridine derivatives was conducted in an attempt to discover N-type calcium channel blockers that were highly selective over L-type calcium channel blockers. Among the tested compounds, (+)-4-(3,5-dichloro-4-methoxy-phenyl)-1,4-dihydro-pyridine-3,5-dicarboxylic acid 3-cinnamyl ester was found to be an effective and selective N-type calcium channel blocker with oral analgesic potential.
Subject(s)
Analgesics/chemistry , Calcium Channel Blockers/chemistry , Calcium Channels, N-Type/chemistry , Carboxylic Acids/chemistry , Dihydropyridines/chemistry , Administration, Oral , Analgesics/chemical synthesis , Analgesics/pharmacology , Animals , Calcium Channel Blockers/chemical synthesis , Calcium Channel Blockers/pharmacology , Calcium Channels, N-Type/metabolism , Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacology , Drug Evaluation, Preclinical , Formaldehyde/toxicity , Pain Measurement/drug effects , Rats , Structure-Activity RelationshipABSTRACT
An efficient asymmetric synthesis of 1,4-dihydropyridine derivatives is described. The key step is the stereoselective Michael addition using t-butyl ester of L-valine as a chiral auxiliary to achieve good ee (>95% for all the tested experiments) and moderate yield. With this method, (+)-4-(3-chlorophenyl)-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3,5-dicarboxylic acid cinnamyl ester was obtained and was characterized as a promising N-type calcium channel blocker with improved selectivity over L-type compared to its (-)- and racemic isomers.
Subject(s)
Calcium Channels, N-Type/drug effects , Carboxylic Acids/chemical synthesis , Carboxylic Acids/pharmacology , Animals , Carboxylic Acids/chemistry , Cell Line, Tumor , Dihydropyridines/chemical synthesis , Dihydropyridines/chemistry , Dihydropyridines/pharmacology , Humans , Methyl Ethers/chemical synthesis , Methyl Ethers/chemistry , Methyl Ethers/pharmacology , Molecular Structure , Protein Binding/drug effects , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
In order to find an injectable and selective N-type calcium channel blocker, we have performed the structure-activity relationship (SAR) study on the 2-, 5-, and 6-position of 1,4-dihydropyridine-3-carboxylate derivative APJ2708 (2), which is a derivative of Cilnidipine and has L/N-type calcium channel dual inhibitory activities. As a consequence of the optimization, 6-dimethylacetal derivative 7 was found to have an effective inhibitory activity against N-type calcium channels with more than 170-fold lower activity for L-type channel compared to that of APJ2708.
