New thiazole derivatives as potent and selective 5-hydroxytriptamine 3 (5-HT3) receptor agonists for the treatment of constipation

The syntheses and biological evaluation of a series of novel indeno[1,2-d]thiazole derivatives are described. Several groups reported 5-HT(3) receptor agonists which were mainly evaluated for their activities on the von Bezold-Jarisch reflex (B-J reflex). We discovered that tetrahydrothiazolopyridin...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2003-04, Vol.11 (7), p.1493-1502
Main Authors: IMANISHI, Naoki, IWAOKA, Kiyoshi, TSUKAMOTO, Shin-Ichi, MASE, Toshiyasu, KOSHIO, Hiroyuki, NAGASHIMA, Shin-Ya, KAZUTA, Ken-Ichi, OHTA, Mitsuaki, SAKAMOTO, Shuichi, ITO, Hiroyuki, AKUZAWA, Shinobu, KISO, Tetsuo
Format: Article
Language:English
Subjects:
Animals
Biological and medical sciences
Cathartics - chemical synthesis
Cathartics - pharmacology
Cloning, Molecular
Colon - drug effects
Constipation - drug therapy
Defecation - drug effects
Digestive system
Ferrets
Guinea Pigs
Humans
In Vitro Techniques
Magnetic Resonance Spectroscopy
Medical sciences
Muscle Contraction - drug effects
Muscle, Smooth - drug effects
Pharmacology. Drug treatments
Radioligand Assay
Rats
Receptors, Serotonin - drug effects
Receptors, Serotonin, 5-HT3
Recombinant Proteins - metabolism
Reflex - drug effects
Serotonin Receptor Agonists - chemical synthesis
Serotonin Receptor Agonists - pharmacology
Thiazoles - chemical synthesis
Thiazoles - pharmacology
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Summary:The syntheses and biological evaluation of a series of novel indeno[1,2-d]thiazole derivatives are described. Several groups reported 5-HT(3) receptor agonists which were mainly evaluated for their activities on the von Bezold-Jarisch reflex (B-J reflex). We discovered that tetrahydrothiazolopyridine derivative 1b had a contractile effect on the isolated guinea pig colon with weak B-J reflex. Our efforts to find a new type of 5-HT(3) receptor agonists on the isolated guinea pig colon focused on the synthesis of a fused thiazole derivative 1d modified from 1b and reverse-fused thiazole derivatives (7-10). In this series, 10f (YM-31636) showed high affinity and selectivity for the cloned human 5-HT(3) receptor; furthermore, it showed potent and selective 5-HT(3) receptor agonistic activity. YM-31636 was examined for its effects on defecation in animals, thus evaluating the compound as an agent against constipation.
ISSN:0968-0896
1464-3391
DOI:10.1016/s0968-0896(02)00557-6