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N'-(arylsulfonyl)pyrazoline-1-carboxamidines as novel, neutral 5-hydroxytryptamine 6 receptor (5-HT₆R) antagonists with unique structural features.

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.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

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

doi

10.1021/jm200466r

subject

Has Abstract

pub_date

2011-10-27 00:00:00

pages

7030-54

issue

20

eissn

0022-2623

issn

1520-4804

journal_volume

54

pub_type

杂志文章

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