Design and syntheses of a series of novel serotonin3 antagonists.
From a structural comparison study between serotonin and serotonin3 (5-HT3) antagonists using a two-dimensional grid template composed of regular hexagons, we deduced structural modification patterns from agonists to antagonists, and designed new 5-HT3 antagonist prototypes. Among them, 2-(4-methyl-1-piperazinyl)-1-butylbenzimidazole (6) was identified as a lead compound which has potent 5-HT3 antagonistic activity comparable to that of granisetron. Using a quantitative structure-activity relationships method, we optimized the structure of 6 and selected 6-amino-5-chloro-1-isopropyl-2-(4-methyl-1-piperazinyl)benzimidazole dimaleate (69, KB-6933), one of the most potent and long-acting 5-HT3 antagonists, as a candidate drug.
Hori
M
M
New Drug Research Laboratories, Kanebo Ltd., Osaka, Japan.
Suzuki
K
K
Yamamoto
T
T
Nakajima
F
F
Ozaki
A
A
Ohtaka
H
H
D000818:Animals; D015195:Drug Design; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D015394:Molecular Structure; D051381:Rats; D017207:Rats, Sprague-Dawley; D012702:Serotonin Antagonists / Q000138:chemical synthesis*
D012702:Serotonin Antagonists