2-(Pyrrolidin-1-yl)ethyl-3,4-dihydroisoquinolin-1(2H)-one Derivatives as Potent and Selective Histamine-3 Receptor Antagonists

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 H3 receptor antagonists. In particular, compound 39 exhibited potent in vitr...

Full description

Saved in:
Bibliographic Details
Published in:Journal of medicinal chemistry 2012-03, Vol.55 (5), p.2452-2468
Main Authors: Zhou, Dahui, Gross, Jonathan L, Adedoyin, Adedayo B, Aschmies, Suzan B, Brennan, Julie, Bowlby, Mark, Di, Li, Kubek, Katie, Platt, Brian J, Wang, Zheng, Zhang, Guoming, Brandon, Nicholas, Comery, Thomas A, Robichaud, Albert J
Format: Article
Language:English
Subjects:
Animals
Benzamides - chemical synthesis
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 - chemical synthesis
Histamine H3 Antagonists - chemistry
Histamine H3 Antagonists - pharmacology
Humans
In Vitro Techniques
Isoquinolines - chemical synthesis
Isoquinolines - pharmacokinetics
Isoquinolines - pharmacology
Macaca fascicularis
Male
Microsomes, Liver - metabolism
Permeability
Protein Binding
Pyrrolidines - chemical synthesis
Pyrrolidines - pharmacokinetics
Pyrrolidines - pharmacology
Radioligand Assay
Rats
Rats, Long-Evans
Rats, Sprague-Dawley
Receptors, Histamine H3 - metabolism
Recognition (Psychology) - drug effects
Stereoisomerism
Structure-Activity Relationship
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 H3 receptor antagonists. In particular, compound 39 exhibited potent in vitro binding and functional activities at the H3 receptor, good selectivities against other neurotransmitter receptors and ion channels, acceptable pharmacokinetic properties, and a favorable in vivo profile.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm300011d