ChemInform Abstract: Synthesis of the Selective 5-Hydroxytryptamine 4 (5-HT4) Receptor Agonist (+)-(S)-2-Chloro-5-methoxy-4- [5-(2-piperidylmethyl)-1,2,4-oxadiazol-3-yl]aniline

Autor: Naoki Imanishi, Takeshi Suzuki, Kiyoshi Iwaoka, Toshiyasu Mase, Mitsuaki Ohta, Keiji Miyata, Yukinori Nagakura, Hideaki Nakahara
Rok vydání: 2010
Předmět:
Zdroj: ChemInform. 30
ISSN: 1522-2667
0931-7597
Popis: Serotonin (5-hydroxytryptamine, 5-HT) is widely distributed in the central nervous, gastrointestinal, and cardiovascular systems as a neurotransmitter, neuromodulator and hormone. 1—6) The 5-hydroxytryptamine 4 (5-HT4) receptor is distributed from the esophagus to the colon in the gastrointestinal system, and is especially closely related with regulation of gastrointestinal motility. 7) For these reasons, 5-HT 4 agonists are expected to be effective for treatment of gastrointestinal dysfunctions such as diarrhea, constipation, gastroparesis, ileus, reflux esophagitis, and pseudo-obstructions. Most of the reported 5-HT 4 agonists, except for 5-HT derivatives, 8,9) have a benzamide (or other arylcarboxamide) skeleton, 7) but many possess poor selectivity for the 5-HT 4 receptor due to 5-HT3 antagonistic activity. In order to find new 5-HT 4 agonists, we focused on the linker group of the benzamide and synthesized 3-(4-amino-5chloro-2-methoxyphenyl)-1,2,4-oxadiazole derivatives, derived from the Merck 5-HT3 antagonist 1 possessing an oxadiazole ring (Chart 1). 10) Consequently, it was found that a 1,2,4-oxadiazole ring could function as a linker group instead of an amide bond for 5-HT 4 agonists as well as for 5-HT 3 antagonists. Among such derivatives, cyclic amine derivatives (quinuclidines, hexahydropyrrolizines, piperidines, pyrrolidines) having a basic nitrogen atom at the g-position from oxadiazole showed potent 5-HT 4 agonistic activity in the longitudinal muscle myenteric plexus (LMMP) preparation of guinea pig ileum, and especially 3-piperidylmethyl derivative (2) showed a unique profile. In this paper, we report the synthesis, potency, and receptor selectivity of (S)-2-chloro-5methoxy-4-[5-(2-piperidylmethyl)-1,2,4-oxadiazol-3-yl]aniline [2(S)] as a 5-HT 4 agonist.
Databáze: OpenAIRE
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