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

• Published in: Journal of medicinal chemistry Vol. 54; no. 20; pp. 7030 - 7054
• Main Authors: van Loevezijn, Arnold, Venhorst, Jennifer, Iwema Bakker, Wouter I, de Korte, Cor G, de Looff, Wouter, Verhoog, Stefan, van Wees, Jan-Willem, van Hoeve, Martijn, van de Woestijne, Rob P, van der Neut, Martina A. W, Borst, Alice J. M, van Dongen, Maria J. P, de Bruin, Natasja M. W. J, Keizer, Hiskias G, Kruse, Chris G
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.10.2011; Amer Chemical Soc
• Subjects: Amidines - chemical synthesis; Amidines - chemistry; Amidines - pharmacology; Animals; Chemistry, Medicinal; CHO Cells; Cricetinae; Cricetulus; Crystallography, X-Ray; Guinea Pigs; Hepatocytes - metabolism; Humans; In Vitro Techniques; Life Sciences & Biomedicine; Ligands; Magnetic Resonance Spectroscopy; Male; Models, Molecular; Pharmacology & Pharmacy; Protein Binding; Pyrazoles - chemical synthesis; Pyrazoles - chemistry; Pyrazoles - pharmacology; Rats; Rats, Wistar; Receptors, Serotonin - metabolism; Science & Technology; Serotonin Antagonists - chemical synthesis; Serotonin Antagonists - chemistry; Serotonin Antagonists - pharmacology; Stereoisomerism; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; SEROTONIN RECEPTOR; TARGET; HERG; 2ND-GENERATION ANTIHISTAMINES; CRYSTAL-STRUCTURE; DOUBLE-BLIND; SCHIZOPHRENIA; MODEL; IDENTIFICATION; LIGAND-BINDING SITE
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm200466r

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 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-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 42 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.