title: New thiazole derivatives as potent and selective 5-hydroxytriptamine 3 (5-HT3) receptor agonists for the treatment of constipation.
abstract: 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.
authors.affiliation: Institute for Drug Discovery Research,Yamanouchi Pharmaceutical Co., Ltd., 21Miyukigaoka, Tsukuba, Ibaraki, 305-8585, Japan. imanishi@yamanouchi.co.jp
authors.forename: Naoki
authors.initials: N
authors.lastname: Imanishi
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Iwaoka
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Koshio
authors.forename: Shin-ya
authors.initials: SY
authors.lastname: Nagashima
authors.forename: Ken-ichi
authors.initials: K
authors.lastname: Kazuta
authors.forename: Mitsuaki
authors.initials: M
authors.lastname: Ohta
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sakamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Ito
authors.forename: Shinobu
authors.initials: S
authors.lastname: Akuzawa
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Kiso
authors.forename: Shin-ichi
authors.initials: S
authors.lastname: Tsukamoto
authors.forename: Toshiyasu
authors.initials: T
authors.lastname: Mase
mesh_terms: D000818:Animals; D002400:Cathartics / Q000138:chemical synthesis* / Q000494:pharmacology*; D003001:Cloning, Molecular; D003106:Colon / Q000187:drug effects; D003248:Constipation / Q000188:drug therapy*; D003672:Defecation / Q000187:drug effects; D005289:Ferrets; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D011985:Receptors, Serotonin / Q000187:drug effects*; D044406:Receptors, Serotonin, 5-HT3; D011994:Recombinant Proteins / Q000378:metabolism; D012018:Reflex / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000138:chemical synthesis* / Q000494:pharmacology*; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D002400:Cathartics; D011985:Receptors, Serotonin; D044406:Receptors, Serotonin, 5-HT3; D011994:Recombinant Proteins; D017366:Serotonin Receptor Agonists; D013844:Thiazoles