Referenced in: none

Automatically associated channels: Kv11.1

Title: Design, synthesis, and pharmacological evaluation of piperidin-4-yl amino aryl sulfonamides: novel, potent, selective, orally active, and brain penetrant 5-HT₆ receptor antagonists.

Authors: Ramakrishna Nirogi, Anil Shinde, Anand Daulatabad, Ramasastri Kambhampati, Parandhama Gudla, Mohammad Shaik, Muralimohan Gampa, Suresh Balasubramaniam, Pamuletinarasimhareddy Gangadasari, Veena Reballi, Rajeshkumar Badange, Kumar Bojja, Ramkumar Subramanian, Gopinadh Bhyrapuneni, Nageswararao Muddana, Pradeep Jayarajan

Journal, date & volume: J. Med. Chem., 2012 Nov 8 , 55, 9255-69

PubMed link: http://www.ncbi.nlm.nih.gov/pubmed/23006002

Abstract
Our initial findings around aryl sulfonamide series led to N-(3,5-dichloro-2-methoxyphenyl)-3-(1-methylpiperidin-4-ylamino)-4-methoxy benzenesulfonamide as potent and selective 5-HT(6) receptor (5-HT(6)R) antagonist with reasonable pharmacokinetic properties and activity in animal models of cognition. However, lack of brain penetration and P-glycoprotein liability makes this scaffold unsuitable for further development. Our goal was to identify small molecule 5-HT(6)R antagonist with adequate brain penetration, acceptable ADME properties, no P-glycoprotein, and no hERG liability. Several structural modifications including bringing conformational constraint around the sulfonamide -NH group and introduction of a heteroatom to modulate the physicochemical properties were attempted. This effort culminated in the discovery of series of novel, potent, selective, orally bioavailable, and adequately brain penetrant compounds with no hERG liability. These compounds showed activity in animal models of cognition like object recognition task and water maze and in brain microdialysis studies at lower doses.