Synthesis and Structure–Activity Relationship (SAR) of (5,7-Disubstituted 3-phenylsulfonyl-pyrazolo[1,5-a]pyrimidin-2-yl)-methylamines as Potent Serotonin 5-HT6Receptor (5-HT6R) Antagonists

摘要: Syntheses, biological evaluation as 5-HT6 receptor (5-HT6R) antagonists, and structure–activity relationships for a series of novel 5,7-disubstituted (3-arylsulfonyl-pyrazolo[1,5-a]pyrimidins are disclosed. The molecule conformational flexibility in the is restricted by formation intramolecular hydrogen bond between 3-sulfo 2-methylamino groups, which renders high potency selectivity to block serotonin-induced responses HEK-293 cells stably expressing human 5-HT6R. In this work, we tested hypothesis if addition positively ionizable group (PI) pyrimidine ring scaffold members positions 5, 6, or 7 could further increase their 5HT6R blocking potency. We show that presence PI with small substituents does not substantially affect either ligands while causing substantial changes cLogP values. This provides possibility designing modified ADME characteristics without gros...