N'-(arylsulfonyl)pyrazoline-1-carboxamidines as novel, neutral 5-hydroxytryptamine 6 receptor (5-HT(6)R) antagonists with unique structural features.

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van Loevezijn A, Venhorst J, Iwema Bakker WI, de Korte CG, de Looff W, Verhoog S, van Wees JW, van Hoeve M, van de Woestijne RP, van der Neut MA, Borst AJ, van Dongen MJ, de Bruin NM, Keizer HG, Kruse CG

N'-(arylsulfonyl)pyrazoline-1-carboxamidines as novel, neutral 5-hydroxytryptamine 6 receptor (5-HT(6)R) antagonists with unique structural features.

J Med Chem. 2011 Oct 27;54(20):7030-54. doi: 10.1021/jm200466r. Epub 2011 Sep 26.

PubMed ID
21866910 [ View in PubMed
]
Abstract

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.

DrugBank Data that Cites this Article

Drug Targets
DrugTargetKindOrganismPharmacological ActionActions
Lysergic acid diethylamide5-hydroxytryptamine receptor 6ProteinHumans
Unknown
Not AvailableDetails