ABSTRACT
The discovery of non-basic N'-(arylsulfonyl)pyrazoline-1-carboxamidines as 5-HT6 antagonists with unique structural features was recently disclosed. Here we describe how this structural class was further developed by addressing an unexplored interaction site of the 5-HT6 receptor. Compound 13 resulting from this effort is a highly potent and selective 5-HT6 antagonist with improved metabolic stability. It is furthermore devoid of hERG affinity. Despite its modest CNS/plasma ratio, a high brain free fraction ensured substantial exposure to allow for rodent cognition studies.
Subject(s)
Pyrazoles/pharmacology , Receptors, Serotonin/metabolism , Serotonin Antagonists/pharmacology , Sulfonamides/pharmacology , Binding Sites/drug effects , Dose-Response Relationship, Drug , Humans , Molecular Docking Simulation , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/chemistry , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/chemistryABSTRACT
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.
Subject(s)
Amidines/chemical synthesis , Pyrazoles/chemical synthesis , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Sulfonamides/chemical synthesis , Amidines/chemistry , Amidines/pharmacology , Animals , CHO Cells , Cricetinae , Cricetulus , Crystallography, X-Ray , Guinea Pigs , Hepatocytes/metabolism , Humans , In Vitro Techniques , Ligands , Magnetic Resonance Spectroscopy , Male , Models, Molecular , Protein Binding , Pyrazoles/chemistry , Pyrazoles/pharmacology , Rats , Rats, Wistar , Serotonin Antagonists/chemistry , Serotonin Antagonists/pharmacology , Stereoisomerism , Structure-Activity Relationship , Sulfonamides/chemistry , Sulfonamides/pharmacologyABSTRACT
The synthesis and structure-activity relations for a new class of centrally active NK-1 receptor antagonists are described. The new compounds are based on piperazine 2 and contain an oxime ether functionality. Several new compounds have high affinity for the NK-1 receptor and show good antagonistic activity in the gerbil foot-tapping assay.
