Asymmetric synthesis and biological evaluations of (+)- and (−)-6-dimethoxymethyl-1,4-dihydropyridine-3-carboxylic acid derivatives blocking N-type calcium channels

The novel asymmetric synthesis is reported for the preparation of optically pure (+)-4-(3-chlorophenyl)-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3,5-dicarboxilic acid cinnamyl ester ((+)- 3) as a promising blocker for the N-type calcium channels. An efficient asymmetric synthesis of 1,4-dihydr...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2011-06, Vol.21 (11), p.3317-3319
Main Authors: Yamamoto, Takashi, Ohno, Seiji, Niwa, Seiji, Tokumasu, Munetaka, Hagihara, Masako, Koganei, Hajime, Fujita, Shin-ichi, Takeda, Tomoko, Saitou, Yuki, Iwayama, Satoshi, Takahara, Akira, Iwata, Seinosuke, Shoji, Masataka
Format: Article
Language:English
Subjects:
1,4-Dihydropyridine derivative
Animals
Asymmetric synthesis
Biological and medical sciences
calcium channel blockers
calcium channels
Calcium Channels, N-Type - drug effects
Carboxylic Acids - chemical synthesis
Carboxylic Acids - chemistry
Carboxylic Acids - pharmacology
Cell Line, Tumor
Dihydropyridines - chemical synthesis
Dihydropyridines - chemistry
Dihydropyridines - pharmacology
Humans
isomers
Medical sciences
Methyl Ethers - chemical synthesis
Methyl Ethers - chemistry
Methyl Ethers - pharmacology
Miscellaneous
Molecular Structure
N-type calcium channel blocker
Neuropharmacology
Pharmacology. Drug treatments
Protein Binding - drug effects
Rats
Stereoisomerism
Structure-Activity Relationship
Structure–activity relationships
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Summary:The novel asymmetric synthesis is reported for the preparation of optically pure (+)-4-(3-chlorophenyl)-6-dimethoxymethyl-2-methyl-1,4-dihydropyridine-3,5-dicarboxilic acid cinnamyl ester ((+)- 3) as a promising blocker for the N-type calcium channels. 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.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.04.007