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

• 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
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm300011d

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.