(2E,4E)-N-(4-(1H-indol-3-yl)piperidin-1-yl)alkyl-5-(substituted phenyl)-2,4-pentadienamides as antiallergic agents with antihistaminic and anti slow-reacting substance (SRS) activities.
As an extension of our study aiming to discover a novel compound with dual activities against histamine and slow-reacting substance (SRS), we synthesized two types of indolylpiperidine derivatives, 3 and 4-20. Testing for in vivo antianaphylactic activity and for in vitro anti-SRS activity revealed that (2E,4E)-5-(3,5-dimethoxy-4-hydroxyphenyl)-N-(2-(4-(1H-indol-3-yl)+ ++piperidin-1- yl)ethyl)-2,4-pentadienamide (11) exhibited potent dual activities with ED50 = 0.89 mg/kg and IC50 = 1.43 microM, respectively. However, the plasma concentration of unchanged 11 was very low when administered orally in guinea pigs. This result can be explained by fast formation of a glucuronic acid conjugate.
Shigenaga
S
S
New Drug Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Osaka, Japan.
Manabe
T
T
Matsuda
H
H
Fujii
T
T
Matsuo
M
M
D000577:Amides / Q000494:pharmacology*; D000818:Animals; D018926:Anti-Allergic Agents / Q000737:chemistry* / Q000494:pharmacology*; D006168:Guinea Pigs; D007082:Ileum / Q000187:drug effects*; D010880:Piperidines / Q000737:chemistry* / Q000494:pharmacology*; D012867:Skin / Q000187:drug effects*; D013329:Structure-Activity Relationship
D000577:Amides; D018926:Anti-Allergic Agents; D010880:Piperidines