title: Optimization of N'-(arylsulfonyl)pyrazoline-1-carboxamidines by exploiting a novel interaction site in the 5-HT6 antagonistic binding pocket.
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.
authors.affiliation: Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: Arnold
authors.initials: A
authors.lastname: van Loevezijn
authors.affiliation: Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands. Electronic address: jennifer.mccormack@tno.nl.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Venhorst
authors.affiliation: Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: Wouter I
authors.initials: WI
authors.lastname: Iwema Bakker
authors.affiliation: Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: Jos H M
authors.initials: JHM
authors.lastname: Lange
authors.affiliation: Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: Wouter
authors.initials: W
authors.lastname: de Looff
authors.affiliation: Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: Remco
authors.initials: R
authors.lastname: Henzen
authors.affiliation: Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: Jelle
authors.initials: J
authors.lastname: de Vries
authors.affiliation: Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: Rob P
authors.initials: RP
authors.lastname: van de Woestijne
authors.affiliation: Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: Arnold P
authors.initials: AP
authors.lastname: den Hartog
authors.affiliation: Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: Stefan
authors.initials: S
authors.lastname: Verhoog
authors.affiliation: Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: Martina A W
authors.initials: MAW
authors.lastname: van der Neut
authors.affiliation: Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: Natasja M W J
authors.initials: NMWJ
authors.lastname: de Bruin
authors.affiliation: Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands.
authors.forename: Chris G
authors.initials: CG
authors.lastname: Kruse
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D006801:Humans; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D011720:Pyrazoles / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D011720:Pyrazoles; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013449:Sulfonamides; C097216:serotonin 6 receptor
keywords: 5-HT(6) receptor; Molecular modeling; Non-basic 5-HT(6) antagonists; N′-(Arylsulfonyl)pyrazoline-1-carboxamidines