title: Asymmetric synthesis and biological evaluations of (+)- and (-)-6-dimethoxymethyl-1,4-dihydropyridine-3-carboxylic acid derivatives blocking N-type calcium channels.
abstract: 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.
authors.affiliation: Exploratory Research Laboratories, Ajinomoto Pharmaceuticals Co., Ltd, 1-1, Suzuki-cho, Kawasaki-ku, Kawasaki-shi, Kanagawa, Japan. takashia_yamamoto@ajinomoto.com
authors.forename: Takashi
authors.initials: T
authors.lastname: Yamamoto
authors.forename: Seiji
authors.initials: S
authors.lastname: Ohno
authors.forename: Seiji
authors.initials: S
authors.lastname: Niwa
authors.forename: Munetaka
authors.initials: M
authors.lastname: Tokumasu
authors.forename: Masako
authors.initials: M
authors.lastname: Hagihara
authors.forename: Hajime
authors.initials: H
authors.lastname: Koganei
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Fujita
authors.forename: Tomoko
authors.initials: T
authors.lastname: Takeda
authors.forename: Yuki
authors.initials: Y
authors.lastname: Saitou
authors.forename: Satoshi
authors.initials: S
authors.lastname: Iwayama
authors.forename: Akira
authors.initials: A
authors.lastname: Takahara
authors.forename: Seinosuke
authors.initials: S
authors.lastname: Iwata
authors.forename: Masataka
authors.initials: M
authors.lastname: Shoji
mesh_terms: D000818:Animals; D020864:Calcium Channels, N-Type / Q000187:drug effects*; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D004095:Dihydropyridines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008738:Methyl Ethers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D015394:Molecular Structure; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
chemical_list: D020864:Calcium Channels, N-Type; D002264:Carboxylic Acids; D004095:Dihydropyridines; D008738:Methyl Ethers; C038806:1,4-dihydropyridine