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.
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.
authors.affiliation: Discovery Research-Medicinal Chemistry, Suven Life Sciences Ltd., Serene Chambers, Road-5, Avenue-7, Banjara Hills, Hyderabad 500 034, India. nvsrk@suven.com
authors.forename: Ramakrishna
authors.initials: R
authors.lastname: Nirogi
authors.forename: Anil
authors.initials: A
authors.lastname: Shinde
authors.forename: Anand
authors.initials: A
authors.lastname: Daulatabad
authors.forename: Ramasastri
authors.initials: R
authors.lastname: Kambhampati
authors.forename: Parandhama
authors.initials: P
authors.lastname: Gudla
authors.forename: Mohammad
authors.initials: M
authors.lastname: Shaik
authors.forename: Muralimohan
authors.initials: M
authors.lastname: Gampa
authors.forename: Suresh
authors.initials: S
authors.lastname: Balasubramaniam
authors.forename: Pamuletinarasimhareddy
authors.initials: P
authors.lastname: Gangadasari
authors.forename: Veena
authors.initials: V
authors.lastname: Reballi
authors.forename: Rajeshkumar
authors.initials: R
authors.lastname: Badange
authors.forename: Kumar
authors.initials: K
authors.lastname: Bojja
authors.forename: Ramkumar
authors.initials: R
authors.lastname: Subramanian
authors.forename: Gopinadh
authors.initials: G
authors.lastname: Bhyrapuneni
authors.forename: Nageswararao
authors.initials: N
authors.lastname: Muddana
authors.forename: Pradeep
authors.initials: P
authors.lastname: Jayarajan
mesh_terms: D000284:Administration, Oral; D000818:Animals; D001921:Brain / Q000378:metabolism*; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D015195:Drug Design; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D005106:Exploratory Behavior / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D008297:Male; D018782:Maze Learning / Q000187:drug effects; D008862:Microsomes, Liver / Q000378:metabolism; D008968:Molecular Conformation; D010539:Permeability; D010880:Piperidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D011985:Receptors, Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology
chemical_list: D065607:Cytochrome P-450 Enzyme Inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D007211:Indoles; C000606913:KCNH2 protein, human; D010880:Piperidines; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D013449:Sulfonamides; C097216:serotonin 6 receptor