Synthesis and Structure鈥揂ctivity Relationship (SAR) of (5,7-Disubstituted 3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methylamines as Potent Serotonin 5-HT6 Receptor (5-HT6<

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• 作者：Alexandre V. Ivachtchenko ; Elena S. Golovina ; Madina G. Kadieva ; Volodymyr M. Kysil ; Oleg D. Mitkin ; Sergey E. Tkachenko ; Ilya M. Okun
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：December 8, 2011
• 年：2011
• 卷：54
• 期：23
• 页码：8161-8173
• 全文大小：590K
• 年卷期：v.54,no.23(December 8, 2011)
• ISSN：1520-4804

文摘

Syntheses, biological evaluation as 5-HT₆ receptor (5-HT₆R) antagonists, and structure鈥揳ctivity relationships for a series of novel 5,7-disubstituted (3-arylsulfonyl-pyrazolo[1,5-a]pyrimidins are disclosed. The molecule conformational flexibility in the series is restricted by formation of the intramolecular hydrogen bond between 3-sulfo and 2-methylamino groups, which renders high potency and high selectivity to block serotonin-induced responses in HEK-293 cells stably expressing human 5-HT₆R. In this work, we tested the hypothesis if addition of a positively ionizable group (PI) to the pyrimidine ring of the scaffold members in positions 5, 6, or 7 could further increase their 5HT₆R blocking potency. We show that the presence of the PI group with small substituents does not substantially affect either potency or selectivity of the ligands while causing substantial changes in their cLogP values. This provides a possibility for designing of the 5HT₆R ligands with modified ADME characteristics without grossly affecting efficiency of their interaction with the receptor. In respect to the structure鈥揳ctivity relationship (SAR), among other physiochemical parameters, only the molecule size and shape (described by gyration radii) showed a clear tendency for more compact molecules to be more potent antagonists of this receptor.