ABSTRACT
On the basis of the previously reported benzimidazole 1,3'-bipyrrolidine benzamides (1), a new class of 2-(pyrrolidin-1-yl)ethyl-3,4-dihydroisoquinolin-1(2H)-one derivatives (3-50) were synthesized and evaluated as potent H(3) receptor antagonists. In particular, compound 39 exhibited potent in vitro binding and functional activities at the H(3) receptor, good selectivities against other neurotransmitter receptors and ion channels, acceptable pharmacokinetic properties, and a favorable in vivo profile.
Subject(s)
Benzamides/chemical synthesis , Histamine H3 Antagonists/chemical synthesis , Isoquinolines/chemical synthesis , Pyrrolidines/chemical synthesis , Receptors, Histamine H3/metabolism , Animals , Benzamides/pharmacokinetics , Benzamides/pharmacology , Blood Proteins/metabolism , Cell Line , Cytochrome P-450 Enzyme Inhibitors , Dogs , Drinking Behavior/drug effects , Drug Inverse Agonism , ERG1 Potassium Channel , Ether-A-Go-Go Potassium Channels/antagonists & inhibitors , Guinea Pigs , Histamine Agonists/chemical synthesis , Histamine Agonists/pharmacokinetics , Histamine Agonists/pharmacology , Histamine H3 Antagonists/chemistry , Histamine H3 Antagonists/pharmacology , Humans , In Vitro Techniques , Isoquinolines/pharmacokinetics , Isoquinolines/pharmacology , Macaca fascicularis , Male , Microsomes, Liver/metabolism , Permeability , Protein Binding , Pyrrolidines/pharmacokinetics , Pyrrolidines/pharmacology , Radioligand Assay , Rats , Rats, Long-Evans , Rats, Sprague-Dawley , Recognition, Psychology/drug effects , Stereoisomerism , Structure-Activity RelationshipABSTRACT
On the basis of the previously reported benzimidazole 1,3'-bipyrrolidine benzamides (1), a series of related pyrrolidin-3-yl-N-methylbenzamides were synthesized and evaluated as H(3) receptor antagonists. In particular, compound 32 exhibits potent H(3) receptor binding affinity, improved pharmaceutical properties and a favorable in vivo profile.
Subject(s)
Benzamides/chemical synthesis , Benzamides/pharmacology , Drug Design , Histamine H3 Antagonists/chemical synthesis , Histamine H3 Antagonists/pharmacology , Pyrrolidines/chemical synthesis , Pyrrolidines/pharmacology , Animals , Benzamides/chemistry , Benzamides/pharmacokinetics , Brain/metabolism , Cognition Disorders/drug therapy , Cognition Disorders/physiopathology , Diabetes Insipidus/drug therapy , Diabetes Insipidus/metabolism , Disease Models, Animal , Histamine H3 Antagonists/chemistry , Histamine H3 Antagonists/pharmacokinetics , Histocompatibility Antigens/metabolism , Humans , Intracellular Signaling Peptides and Proteins , Microsomes, Liver/metabolism , Molecular Targeted Therapy , Protein Binding , Pyrrolidines/chemistry , Pyrrolidines/pharmacokinetics , Rats , Stereoisomerism , Structure-Activity Relationship , Tripartite Motif ProteinsABSTRACT
Using a focused screen of biogenic amine compounds we identified a novel series of H(3)R antagonists. A preliminary SAR study led to reduction of MW while increasing binding affinity and potency. Optimization of the physical properties of the series led to (S)-6n, with improved brain to plasma exposure and efficacy in both water intake and novel object recognition models.
Subject(s)
Benzamides/chemistry , Benzimidazoles/chemistry , Histamine H3 Antagonists/chemistry , Pyrrolidines/chemistry , Receptors, Histamine H3 , Animals , Benzamides/blood , Benzamides/metabolism , Benzimidazoles/blood , Benzimidazoles/metabolism , Caco-2 Cells , Cell Line , Histamine H3 Antagonists/blood , Histamine H3 Antagonists/metabolism , Humans , Indoles/blood , Indoles/chemistry , Indoles/metabolism , Protein Binding , Pyrrolidines/blood , Pyrrolidines/metabolism , Rats , Receptors, Histamine H3/blood , Receptors, Histamine H3/metabolismABSTRACT
Structural modifications of the initial lead, 3-aminochroman (4), led to the identification of a novel series of pyridyl-fused amino chroman derivatives (5-8) and the structural isomers (9-12). The compounds described were evaluated for dual 5-HT transporter inhibitory and 5-HT(1A) receptor activities. The design strategy, synthesis, and in vitro biological characterization for these novel compounds are described.
