Synthesis and pharmacological evaluation of aryl aminosulfonamide derivatives as potent 5-HT 6 receptor antagonists Ramakrishna V. S. Nirogi a, * , Anand V. Daulatabad a , G. Parandhama a , Shaikh Mohammad a , K. R. Sastri a , Anil K. Shinde a , P. K. Dubey b a Discovery Research, Suven Life Sciences Ltd, Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India b Department of Chemistry, Jawaharlal Nehru Technological University Hyderabad, Kukatpally, Hyderabad 500 072, India article info Article history: Received 20 January 2010 Revised 20 May 2010 Accepted 9 June 2010 Available online 12 June 2010 Keywords: 5-HT 6 R NORT Morris water maze Cognition abstract A series of novel aryl aminosulfonamides was designed and synthesized as 5-HT 6 receptor ligands. Many compounds screened in a functional reporter gene based assay displayed potent antagonistic activity with Kb values in the range of 0.02–10 nM. The lead compound 11m exemplified in this series showed good ADME surrogate properties, acceptable pharmacokinetic profile and is active in animal models of cognition like novel object recognition test and Morris water maze. The compound was selected for detailed profiling. Ó 2010 Elsevier Ltd. All rights reserved. Identification of ligands for the 5-hydroxytryptamine 6 receptor (5-HT 6 R) has been the focus of several reports in the last decade. 1–9 Ligands for the 5-HT 6 R may be useful in the treatment of CNS disorders such as schizophrenia, depression, Alzheimer’s disease (AD) 10–14 and metabolic disorders like obesity. Research efforts from several groups, worldwide, have led to the discovery of several clas- ses of serotonin 5-HT 6 receptor ligands 5,15–18 with high affinity and selectivity. Several lead molecules like SB-742457 and SUVN-502 for cognition, PRX-07034 for obesity and LY-483518 (SGS-518) for schizophrenia are in advanced stages of clinical studies. For all these compounds positive clinical study data have been reported in liter- ature. 19–22 A common feature in many of these compound classes is the presence of basic amine functionality, which imparts potent binding site to the 5-HT 6 receptor and a second aryl moiety, which maintains the selectivity over other receptors. All the reported compounds by Glaxo Smithkline contain char- acteristic monocyclic aryl piperazine SB-399885 (compound 1) or herteroaryl piperazine SB-742457 moiety as essential part of their structure. SB-399885 was active in animal model of cognition and SB-742457 is advanced into clinical studies. Most recently 4 scientists at Abbott disclosed their various efforts to modulate the brain penetration by changing the overall lipophilicity of the molecule (compound 2). There was an attempt to decrease the electron density around sulfonamide moiety by incorporating a difluoromethylene unit in aryl sulfonamide side chain. There was measurable impact on brain penetrations with these attempts. As can be seen in 2, these analogues were closely related to SB-399885. LY-483518, which was developed at Lilly for the treatment of cognitive impairment associated with schizophrenia, contains 3- piperadinyl indole as essential pharmacophore, confirming the importance of tertiary nitrogen on piperidine for receptor binding and affinity. N H O 2 S O N NH S O 2 H N O N NH O F F N H O 2 S O H N N 1 (SB-399885) K b = 0.25 nM 2 (Abbott) Ki < 10 nM 11m K b = 0.02 nM O Cl Cl Cl Cl O N O S O 2 3 LY-483518 N F F A B Based on the above observations, we hypothesized that a basic amine function, like the terminal nitrogen of piperazine (as in 0960-894X/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved. doi:10.1016/j.bmcl.2010.06.060 * Corresponding author. Tel.: +91 40 23556038/23541142; fax: +91 40 23541152. E-mail address: ramakrishna_nirogi@yahoo.co.in (R.V.S. Nirogi). Bioorganic & Medicinal Chemistry Letters 20 (2010) 4440–4443 Contents lists available at ScienceDirect Bioorganic & Medicinal Chemistry Letters journal homepage: www.elsevier.com/locate/bmcl