ABSTRACT
The design, synthesis and SAR of novel tetrahydrocarbazole derivatives having 5-HT(6) receptor antagonist activity is presented. The racemic compound 15e was found to possess desirable pharmacokinetic properties, adequate brain penetration and activity in animal models of cognition.
Subject(s)
Amines/chemistry , Carbazoles/chemistry , Receptors, Serotonin/chemistry , Serotonin Antagonists/chemistry , Sulfonamides/chemistry , Amines/chemical synthesis , Amines/pharmacokinetics , Animals , Brain/metabolism , Carbazoles/chemical synthesis , Carbazoles/pharmacokinetics , Half-Life , Humans , Male , Microsomes, Liver/metabolism , Rats , Rats, Wistar , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacokinetics , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokineticsABSTRACT
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.
Subject(s)
Brain/metabolism , Piperidines/chemical synthesis , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Sulfonamides/chemical synthesis , Administration, Oral , Animals , Cytochrome P-450 Enzyme Inhibitors , Dogs , Drug Design , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Exploratory Behavior/drug effects , Humans , Indoles/chemical synthesis , Indoles/pharmacokinetics , Indoles/pharmacology , Male , Maze Learning/drug effects , Microsomes, Liver/metabolism , Molecular Conformation , Permeability , Piperidines/pharmacokinetics , Piperidines/pharmacology , Rats , Rats, Wistar , Serotonin Antagonists/pharmacokinetics , Serotonin Antagonists/pharmacology , Structure-Activity Relationship , Sulfonamides/pharmacokinetics , Sulfonamides/pharmacologyABSTRACT
5-Hydroxytryptamine 6 receptors (5-HT(6)R) are being perceived as the possible target for treatment of cognitive disorders as well as obesity. The present article deals with the design, synthesis, in vitro binding and structure-activity relationship of a novel series of tetracyclic tryptamines with the rigidized N-arylsulphonyl, N-arylcarbonyl and N-benzyl substituents as 5-HT(6) receptor ligands. The chiral sulphonyl derivatives 15a and 17a showed high affinity at 5-HT(6)R with the K(i) of 23.4 and 20.5 nM, respectively. The lead compound from the series 15a has acceptable ADME properties, adequate brain penetration and is active in animal models of cognition like Novel Object Recognition Task (NORT) and water maze.
Subject(s)
Drug Design , Receptors, Serotonin/metabolism , Serotonin/analogs & derivatives , Serotonin/chemistry , Dose-Response Relationship, Drug , Humans , Ligands , Molecular Conformation , Structure-Activity RelationshipABSTRACT
A series of novel conformationally restricted N(1)-arylsulfonyl-3-aminoalkoxy indoles were designed and synthesized as 5-HT(6) receptor (5-HT(6)R) ligands. Many of the synthesized compounds have moderate in vitro-binding affinities at 5-HT(6)R. The lead compound 8b (% inhibition = 97.2 at 1 µM) from this series has good pharmacokinetic profile in male Wister rats and is active in animal model of cognition like Morris water maze. The details of chemistry, SAR, pharmacokinetics and pharmacological data constitute the subject matter of this report.
