- Design and synthesis of piperazinylpyridine derivatives as novel 5-HT 1A agonists/5-HT3 antagonists for the treatment of irritable bowel syndrome (IBS)
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We have prepared a series of piperazinylpyridine derivatives for the treatment of irritable bowel syndrome (IBS). These compounds, which were designed by pharmacophore analysis, bind to both serotonin subtype 1A (5-HT 1A) and subtype 3 (5-HT3) receptors. The nitrogen atom of the isoquinoline, a methoxy group and piper-azine were essential to the pharmacophore for binding to these receptors. We also synthesized furo- and thienopyridine derivatives according to structure-activity relationship analyses. Compound 17c (TZB-20810) had high affinities to these receptors and exhibited 5-HT1A agonistic activity and 5-HT3 antagonistic activity concurrently, and is a promising drug for further development in the treatment of IBS.
- Asagarasu, Akira,Matsui, Teruaki,Hayashi, Hiroyuki,Tamaoki, Satoru,Yamauchi, Yukinao,Sato, Michitaka
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experimental part
p. 34 - 42
(2009/07/18)
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- PYRIMIDINE DERIVATIVE
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This invention provides pyrimidine derivatives represented by a formula, in the formula, ring A stands for carbocyclic group or heterocyclic group, X 1 stands for hydrogen, lower alkyl, amino, etc., X 2 stands for hydrogen or lower alkyl, Y stands for a direct bond or sulfur or nitrogen, n stands for an integer of 0 - 4, and Ar stands for a group of the following formula, or a salt thereof, which concurrently exhibit 5-HT 1A agonistic activity and 5-HT 3 antagonistic activity and are useful for therapy and treatments of diseases such as IBS. The invention furthermore provides a therapeutic method of IBS, characterized by having 5-HT 1A agonistic activity and 5-HT 3 antagonistic activity work simultaneously and cooperatively in vivo, which comprises either administering 5-HT 3 antagonistic agent which concurrently exhibits 5-HT 1A agonistic activity, or administering 5-HT 1A agonistic agent and 5-HT 3 antagonistic agent simultaneously, in sequence or at an interval.
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Page/Page column 91
(2010/11/24)
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- Pyridine compounds
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A compound selected from those of formula (I): wherein: W represents optionally substituted naphthyl, n represents an integer from 2 to 3 inclusive, Z represents a single bond, A represents nitrogen, Q represents nitrogen, M, together with the carbon of pyridyl to which it is bonded, represents thieno, furo, pyrrolo or oxopyrrolo, Its optical isomers and pharmaceutically-acceptable acid or base additional salts thereof, and Medicinal products containing the same which are useful in the treatment of CNS disorders. It being understood that “aryl” is phenyl, naphthyl, dihydronaphthyl, or tetrahydronaphthyl.
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- The Thienopyridine and Furopyridine Rings: New Pharmacophores with Potential Antipsychotic Activity
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Two new arylpiperazine derivatives, the 4-(1-piperazinyl)thieno- and -furopyridine ring systems, have been synthesized and appended via tetramethylene chains to various imide rings.Target compounds from each series were found to have significant activity in the blockade of apomorphine stereotypy and apomorphine-induced climbing, the Sidman avoidance response, and the conditioned avoidance response.In addition, while potent affinity for serotonin 5-HT1 and 5-HT2 receptors was observed for both the thieno- and furopyridine derivatives,the interaction of these molecules with the dopamine D2 receptor was weak.Electrophysiological studies of the lead prototypes from each series, involving compounds 22 and 33, indicate these two molecules have distinctively different effects on dopamine neurons in areas A9 and A10.Despite the similarity these molecules share in their behavioral indices of antipsychotic acivity, it is likely that the thieno- and furopyridine rings employ different mechanisms to achieve this convergence of biological effects.
- New, James S.,Christopher, William L.,Yevich, Joseph P.,Butler, Rhett,Schlemmer, R. Francis,et al.
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p. 1147 - 1156
(2007/10/02)
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