Structure–activity relationship study of 1,4-dihydropyridine derivatives blocking N-type calcium channels

The structure–activity relationship studies of 1,4-dihydropyridine-3-carboxylic acid derived N-type calcium channel blockers were reported. As a consequence of this study, we found orally active 4-(3-chloro-phenyl)-2-methyl-6-trifluoromethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 5-(3,3-diphenylp...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry letters 2006-02, Vol.16 (4), p.798-802
Main Authors: Yamamoto, Takashi, Niwa, Seiji, Ohno, Seiji, Onishi, Tomoyuki, Matsueda, Hiroyuki, Koganei, Hajime, Uneyama, Hisayuki, Fujita, Shin-ichi, Takeda, Tomoko, Kito, Morikazu, Ono, Yukitsugu, Saitou, Yuki, Takahara, Akira, Iwata, Seinosuke, Shoji, Masataka
Format: Article
Language:English
Subjects:
1,4-Dihydropyridine
Analgesic
Analgesics
Animals
Biological and medical sciences
Calcium Channel Blockers - chemical synthesis
Calcium Channel Blockers - chemistry
Calcium Channel Blockers - pharmacology
Calcium Channels, N-Type - drug effects
Cilnidipine
Dihydropyridines - chemical synthesis
Dihydropyridines - chemistry
Dihydropyridines - pharmacology
Formaldehyde - chemistry
Medical sciences
Molecular Structure
N-type calcium channels blocker
Neuropharmacology
Neuroprotective agent
Pain - chemically induced
Pain - drug therapy
Pain Measurement - drug effects
Pharmacology. Drug treatments
Rats
Structure-Activity Relationship
Structure–activity relationship study
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Summary:The structure–activity relationship studies of 1,4-dihydropyridine-3-carboxylic acid derived N-type calcium channel blockers were reported. As a consequence of this study, we found orally active 4-(3-chloro-phenyl)-2-methyl-6-trifluoromethyl-1,4-dihydropyridine-3,5-dicarboxylic acid 5-(3,3-diphenylpropyl) ester ( 21b). Cilnidipine is a 1,4-dihydropyridine derived L/N-type calcium channel dual blocker possessing neuroprotective and analgesic effects which are related to its N-type calcium channel inhibitory activity. In order to find specific N-type calcium channel blockers with the least effects on cardiovascular system, we performed structure–activity relationship study on APJ2708, which is a derivative of cilnidipine, and found a promising N-type calcium channel blocker 21b possessing analgesic effect in vivo with a 1600-fold lower activity against L-type calcium channels than that of cilnidipine.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2005.11.021