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 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.
Pfizer Global Research and Development, 445 Eastern Point Road, Groton, Connecticut 06340, USA. dahui.zhou@pfizer.com
Dahui
D
Zhou
Jonathan L
JL
Gross
Adedayo B
AB
Adedoyin
Suzan B
SB
Aschmies
Julie
J
Brennan
Mark
M
Bowlby
Li
L
Di
Katie
K
Kubek
Brian J
BJ
Platt
Zheng
Z
Wang
Guoming
G
Zhang
Nicholas
N
Brandon
Thomas A
TA
Comery
Albert J
AJ
Robichaud
D000818:Animals; D001549:Benzamides / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D001798:Blood Proteins / Q000378:metabolism; D002460:Cell Line; D065607:Cytochrome P-450 Enzyme Inhibitors; D004285:Dogs; D004327:Drinking Behavior / Q000187:drug effects; D054314:Drug Inverse Agonism; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D017442:Histamine Agonists / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology; D054828:Histamine H3 Antagonists / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D008252:Macaca fascicularis; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D010539:Permeability; D011485:Protein Binding; D011759:Pyrrolidines / Q000138:chemical synthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D020318:Rats, Long-Evans; D017207:Rats, Sprague-Dawley; D018100:Receptors, Histamine H3 / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D001549:Benzamides; D001798:Blood Proteins; D065607:Cytochrome P-450 Enzyme Inhibitors; D000072237:ERG1 Potassium Channel; D051638:Ether-A-Go-Go Potassium Channels; D017442:Histamine Agonists; D054828:Histamine H3 Antagonists; D007546:Isoquinolines; C573300:N,N-dimethyl-4-(1-oxo-2-(2-pyrrolidin-1-ylethyl)-1,2,3,4-tetrahydroisoquinolin-6-yl)benzamide; D011759:Pyrrolidines; D018100:Receptors, Histamine H3; C039109:isoquinoline