title: 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.
authors.affiliation: Abbott Healthcare Products B.V. (formerly Solvay Pharmaceuticals B.V. ), C. J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands. arnold.vanloevezijn@online.nl
authors.forename: Arnold
authors.initials: A
authors.lastname: van Loevezijn
authors.forename: Jennifer
authors.initials: J
authors.lastname: Venhorst
authors.forename: Wouter I
authors.initials: WI
authors.lastname: Iwema Bakker
authors.forename: Cor G
authors.initials: CG
authors.lastname: de Korte
authors.forename: Wouter
authors.initials: W
authors.lastname: de Looff
authors.forename: Stefan
authors.initials: S
authors.lastname: Verhoog
authors.forename: Jan-Willem
authors.initials: JW
authors.lastname: van Wees
authors.forename: Martijn
authors.initials: M
authors.lastname: van Hoeve
authors.forename: Rob P
authors.initials: RP
authors.lastname: van de Woestijne
authors.forename: Martina A W
authors.initials: MA
authors.lastname: van der Neut
authors.forename: Alice J M
authors.initials: AJ
authors.lastname: Borst
authors.forename: Maria J P
authors.initials: MJ
authors.lastname: van Dongen
authors.forename: Natasja M W J
authors.initials: NM
authors.lastname: de Bruin
authors.forename: Hiskias G
authors.initials: HG
authors.lastname: Keizer
authors.forename: Chris G
authors.initials: CG
authors.lastname: Kruse
mesh_terms: D000578:Amidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D018360:Crystallography, X-Ray; D006168:Guinea Pigs; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008958:Models, Molecular; D011485:Protein Binding; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology
chemical_list: D000578:Amidines; D008024:Ligands; C568949:N'-(3-chlorophenylsulfonyl)-N-ethyl-4,4-dimethyl-4,5-dihydro-1H-pyrazole-1-carboxamidine; D011720:Pyrazoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013449:Sulfonamides; C097216:serotonin 6 receptor