<i>N</i>′-(Arylsulfonyl)pyrazoline-1-carboxamidines as Novel, Neutral 5-Hydroxytryptamine 6 Receptor (5-HT₆R) Antagonists with Unique Structural Features

The 5-HT₆ receptor (5-HT₆R) has been in the spotlight for several years regarding CNS-related diseases. We set out to discover novel, neutral 5-HT₆R antagonists to improve off-target selectivity compared to basic amine-containing scaffolds dominating the field. High-throughput screening identified the <i>N</i>′-(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 <b>1</b>–<b>49</b>) displaying high 5-HT₆R 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 <b>42</b> is an extremely selective, hERG-free, high-affinity 5-HT₆R antagonist showing good human in vitro metabolic stability. Rat pharmacokinetic data were sufficiently good to enable further in vivo profiling