Optimization of N 0 -(arylsulfonyl)pyrazoline-1-carboxamidines by exploiting a novel interaction site in the 5-HT 6 antagonistic binding pocket Arnold van Loevezijn y,à , Jennifer Venhorst ⇑,y,§ , Wouter I. Iwema Bakker – , Jos H. M. Lange k , Wouter de Looff yy , Remco Henzen, Jelle de Vries àà , Rob P. van de Woestijne, Arnold P. den Hartog §§ , Stefan Verhoog –– , Martina A. W. van der Neut kk , Natasja M. W. J. de Bruin yyy , Chris G. Kruse ààà Abbott Healthcare Products B.V. (Formerly Solvay Pharmaceuticals B.V.), C.J. van Houtenlaan 36, 1381 CP Weesp, The Netherlands article info Article history: Received 17 December 2015 Revised 30 January 2016 Accepted 1 February 2016 Available online 2 February 2016 Keywords: 5-HT 6 receptor N 0 -(Arylsulfonyl)pyrazoline-1- carboxamidines Non-basic 5-HT 6 antagonists Molecular modeling abstract The discovery of non-basic N 0 -(arylsulfonyl)pyrazoline-1-carboxamidines as 5-HT 6 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-HT 6 receptor. Compound 13 resulting from this effort is a highly potent and selective 5-HT 6 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. Ó 2016 Elsevier Ltd. All rights reserved. The treatment of cognitive impairment, particularly that associ- ated with Alzheimer’s disease (AD) and Schizophrenia, constitutes an urgent unmet medical need. Innovative therapies to amelio- rate—or better counteract—cognitive dysfunction is thus highly sought after. In recent years, evidence has mounted for a role of 5-HT 6 receptor inhibition in the treatment of cognitive impair- ment. 1–3 In vivo effects on cognitive functions such as memory acquisition, consolidation and retention have been reported using various rodent cognition models. 4 Pathways by which this G-pro- tein coupled receptor (GPCR) may induce such effects include enhancement of acetylcholine, glutamate and dopamine neuro- transmission 5–7 and neuronal cell adhesion molecule (NCAM)- mediated neuronal remodeling. 8,9 Increased expression of both brain-derived neurotrophic factor (BDNF) and activity-regulated cytoskeletal-associated protein (Arc) have also been linked to blockage of 5-HT 6 signaling. 10 Antagonists of the 5-HT 6 receptor thus hold promise for causal treatment of cognitive impairment, besides symptomatic relief. Combination therapy with an acetyl- choline esterase inhibitor (e.g., Donepezil), currently the predomi- nant marketed therapy for AD, may also have added benefit. 11,12 Early generation 5-HT 6 antagonists centered around basic nitro- gen-containing cores. 13–16 Nevertheless, an in-house HTS cam- paign identified a privileged structure possessing substantial inhibitory activity despite the lack of an ionizable nitrogen. 17 Molecular modeling supported by X-ray and NMR data revealed unique structural features of this sulfonylpyrazoline carboxamidine core (Fig. 1). 17 These include the presence of a pseudo-aromatic core and an internal hydrogen bond locking the antagonists in the bioactive conformation. Benefits of neutral http://dx.doi.org/10.1016/j.bmcl.2016.02.001 0960-894X/Ó 2016 Elsevier Ltd. All rights reserved. ⇑ Corresponding author. Tel.: +31 88 866 2586. E-mail address: jennifer.mccormack@tno.nl (J. Venhorst). y Both authors contributed equally to this work. à Current address: Albemarle Catalysts Company B.V., Nieuwendammerkade 1–3, 1022 AB Amsterdam, The Netherlands. § Current address: TNO, Utrechtseweg 48, 3704 HE Zeist, The Netherlands. – Current address: CBG, Graadt van Roggenweg 500, 3531 AH Utrecht, The Netherlands. k Current address: Arizona Chemical B.V., Transistorstraat 16, 1322 CE Almere, The Netherlands. yy Current address: TMC, Flight Forum 107, 5657 DC Eindhoven, The Netherlands. àà Current address: AvL/NKI, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands. §§ Current address: Shell Global Solutions, Grasweg 31, 1031 HW Amsterdam, The Netherlands. –– Current address: Oxford University, Wellington Square, Oxford OX1 2JD, United Kingdom. kk Current address: Enza Zaden, Haling 1/E, 1602 DB Enkhuizen, The Netherlands. yyy Current address: Fraunhofer Institute for Molecular Biology and Applied Ecology IME, Project Group Translational Medicine & Pharmacology TMP, Theodor-Stern-Kai 7, 60596 Frankfurt am Main, Germany. ààà Current address: SILS/University of Amsterdam, Sciencepark 904, 1098 XH Amsterdam, The Netherlands. Bioorganic & Medicinal Chemistry Letters 26 (2016) 1605–1611 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl