ABSTRACT
4-(Piperazin-1-yl methyl)-N(1)-arylsulfonyl indole derivatives were designed and synthesized as 5-HT(6) receptor (5-HT(6)R) ligands. The lead compound 6a, from this series shows potent in vitro binding affinity, good PK profile, no CYP liabilities and activity in animal models of cognition.
Subject(s)
Drug Design , Enzyme Inhibitors/pharmacology , Indoles/pharmacology , Receptors, Serotonin/metabolism , Animals , Cytochrome P-450 CYP2D6/metabolism , Cytochrome P-450 CYP2D6 Inhibitors , Cytochrome P-450 CYP3A/metabolism , Cytochrome P-450 CYP3A Inhibitors , Dose-Response Relationship, Drug , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , HEK293 Cells , Humans , Indoles/chemical synthesis , Indoles/chemistry , Ligands , Male , Molecular Structure , Rats , Rats, Wistar , Structure-Activity RelationshipABSTRACT
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.
Subject(s)
Drug Design , Indoles/pharmacology , Receptors, Serotonin/chemistry , Animals , Cognition/drug effects , Dose-Response Relationship, Drug , Indoles/chemical synthesis , Indoles/chemistry , Ligands , Male , Models, Animal , Molecular Conformation , Rats , Rats, Wistar , Stereoisomerism , Structure-Activity RelationshipABSTRACT
N(1)-Arylsulfonyl-3-piperazinyl indole derivatives were designed and identified as a novel class of 5-HT(6) receptors ligands. All the compounds have high affinity and antagonist activity towards 5-HT(6) receptor. The compound 7a (K(i) = 3.4 nM, functional assay IC(50) = 310 nM) shows enhanced cognitive effect when tested in NORT and Morris water maze models. Synthesis, SAR and PK profile of these novel compounds constitute the subject matter of this Letter.
Subject(s)
Indoles/chemistry , Piperazines/chemistry , Receptors, Serotonin/chemistry , Serotonin Antagonists/chemistry , Sulfonamides/chemistry , Administration, Oral , Animals , Humans , Indoles/chemical synthesis , Indoles/pharmacokinetics , Male , Microsomes, Liver/metabolism , Piperazines/chemical synthesis , Piperazines/pharmacokinetics , Protein Binding , Rats , Rats, Wistar , Receptors, Serotonin/metabolism , Serotonin Antagonists/chemical synthesis , Serotonin Antagonists/pharmacokinetics , Structure-Activity Relationship , Sulfonamides/chemical synthesis , Sulfonamides/pharmacokineticsABSTRACT
The exclusive distribution of 5-HT6 receptors in the brain regions associated with learning and memory makes it an ideal target for cognitive disorders. A novel series of 5-piperazinyl methyl-N 1-aryl sulfonyl indoles were designed and synthesized as 5-HT6R ligands. Most of the synthesized compounds are potent when tested by in vitro radioligand binding assay. The lead compound from the series does not have the CYP liabilities and is active in an animal model of cognition.
ABSTRACT
The synthesis and potential 5-hydroxytryptamine(6) receptor (5-HT6R) antagonist activity of a novel series of N-arylsulfonyl-3-(2-N,N-dimethylaminoethylthio) indoles has been reported. The molecular modeling, synthesis and in-vitro radioligand binding data of this series are discussed. The present article describes 37 derivatives of the title series. It was observed that the increased side-chain length with the insertion of a sulfur atom did not lead to the loss of binding affinity of these compounds, although the affinities were reduced. The compounds exhibited moderate affinity and selectivity to human 5-HT6 receptors.