N'-(arylsulfonyl)pyrazoline-1-carboxamidines as novel, neutral 5-hydroxytryptamine 6 receptor (5-HT₆R) antagonists with unique structural features
| Autor: | Arnold, van Loevezijn, Jennifer, Venhorst, Wouter I, Iwema Bakker, Cor G, de Korte, Wouter, de Looff, Stefan, Verhoog, Jan-Willem, van Wees, Martijn, van Hoeve, Rob P, van de Woestijne, Martina A W, van der Neut, Alice J M, Borst, Maria J P, van Dongen, Natasja M W J, de Bruin, Hiskias G, Keizer, Chris G, Kruse |
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| Rok vydání: | 2011 |
| Předmět: |
Male
Models Molecular Sulfonamides Magnetic Resonance Spectroscopy Guinea Pigs Amidines Stereoisomerism CHO Cells In Vitro Techniques Crystallography X-Ray Ligands Rats Structure-Activity Relationship Cricetulus Cricetinae Receptors Serotonin Hepatocytes Animals Humans Pyrazoles Serotonin Antagonists Rats Wistar Protein Binding |
| Zdroj: | Journal of medicinal chemistry. 54(20) |
| ISSN: | 1520-4804 |
| Popis: | The 5-HT(6) receptor (5-HT(6)R) has been in the spotlight for several years regarding CNS-related diseases. We set out to discover novel, neutral 5-HT(6)R antagonists to improve off-target selectivity compared to basic amine-containing scaffolds dominating the field. High-throughput screening identified the N'-(sulfonyl)pyrazoline-1-carboxamidine scaffold as a promising neutral core for starting hit-to-lead. Medicinal chemistry, molecular modeling, small molecule NMR and X-ray crystallography were subsequently applied to optimize the leads into antagonists (compounds 1-49) displaying high 5-HT(6)R affinity with optimal off-target selectivity. Unique structural features include a pseudoaromatic system and an internal hydrogen bond freezing the bioactive conformation. While physicochemical properties and CNS availability were generally favorable, significant efforts had to be made to improve metabolic stability. The optimized structure 42 is an extremely selective, hERG-free, high-affinity 5-HT(6)R antagonist showing good human in vitro metabolic stability. Rat pharmacokinetic data were sufficiently good to enable further in vivo profiling. |
| Databáze: | OpenAIRE |
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