title: Structure-activity study of L-amino acid-based N-type calcium channel blockers.
abstract: Synthesis and structure-activity relationship (SAR) study of L-amino acid-based N-type calcium channel blockers are described. The compounds synthesized were evaluated for inhibitory activity against both N-type and L-type calcium channels focusing on selectivity to reduce cardiovascular side effects due to blocking of L-type calcium channels. In the course of screening of our compound library, N-(t-butoxycarbonyl)-L-aspartic acid derivative 1a was identified as an initial lead compound for a new series of N-type calcium channel blockers, which inhibited calcium influx into IMR-32 human neuroblastoma cells with an IC(50) of 3.4 microM. Compound 1a also exhibited blockade of N-type calcium channel current in electrophysiological experiment using IMR-32 cells (34% inhibition at 10 microM, n=3). As a consequence of conversion of amino acid residue of 1a, compound 12a, that include N-(t-butoxycarbonyl)-L-cysteine, was found to be a potent N-type calcium channel blocker with an IC(50) of 0.61 microM. Thus, L-cysteine was selected as a potential structural motif for further modification. Optimization of C- and N-terminals of L-cysteine using S-cyclohexylmethyl-L-cysteine as a central scaffold led to potent and selective N-type calcium channel blocker 21f, which showed improved inhibitory potency (IC(50) 0.12 microM) and 12-fold selectivity for N-type calcium channels over L-type channels.
authors.affiliation: Minase Research Institute, Ono Pharmaceutical Co., Ltd., 3-1-1 Sakurai, Shimamoto, Mishima, Osaka 618-8585, Japan. seko@ono.co
authors.forename: Takuya
authors.initials: T
authors.lastname: Seko
authors.forename: Masashi
authors.initials: M
authors.lastname: Kato
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Kohno
authors.forename: Shizuka
authors.initials: S
authors.lastname: Ono
authors.forename: Kazuya
authors.initials: K
authors.lastname: Hashimura
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takimizu
authors.forename: Katsuhiko
authors.initials: K
authors.lastname: Nakai
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Maegawa
authors.forename: Nobuo
authors.initials: N
authors.lastname: Katsube
authors.forename: Masaaki
authors.initials: M
authors.lastname: Toda
mesh_terms: D000596:Amino Acids / Q000737:chemistry* / Q000494:pharmacology*; D000818:Animals; D002118:Calcium / Q000737:chemistry / Q000378:metabolism; D002121:Calcium Channel Blockers / Q000737:chemistry* / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D020864:Calcium Channels, N-Type / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D003545:Cysteine / Q000737:chemistry / Q000494:pharmacology; D004594:Electrophysiology / Q000379:methods; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D009447:Neuroblastoma / Q000378:metabolism; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000737:chemistry / Q000494:pharmacology; D014407:Tumor Cells, Cultured
chemical_list: D000596:Amino Acids; D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D020864:Calcium Channels, N-Type; D013844:Thiazoles; D003545:Cysteine; D002118:Calcium