Discovery and preliminary pharmacology of Sch 37370, a dual antagonist of PAF and histamine.
From a series of amide analogs of the histamine H1 antagonist, azatadine, a potent, orally active, dual platelet-activating factor (PAF) and histamine antagonist, Sch 37370, namely 1-acetyl-4-(8-chloro-5,6-dihydro-11H-benzo- [5,6]cyclohepta[1,2-b]pyridin-11-ylidine)piperidine, was discovered. Sch 37370 selectively inhibits PAF-induced aggregation of human platelets in vitro (IC50 = 0.6 microM), and in vivo inhibits PAF- and histamine-induced bronchospasm in guinea pigs with ED50 values of 6.0 and 2.4 mg/kg p.o., respectively. Sch 37370 is expected to be more efficacious than single mediator antagonists in allergic diseases, such as asthma.
Billah
M M
MM
Department of Chemistry, Schering-Plough Research, Schering-Plough Corporation, Bloomfield, New Jersey 07003.
Egan
R W
RW
Ganguly
A K
AK
Green
M J
MJ
Kreutner
W
W
Piwinski
J J
JJ
Siegel
M I
MI
Villani
F J
FJ
Wong
J K
JK
D006633:Histamine Antagonists / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D017336:Loratadine / Q000031:analogs & derivatives; D008297:Male; D010880:Piperidines / Q000138:chemical synthesis / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship
D006633:Histamine Antagonists; D010880:Piperidines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D017336:Loratadine; C063524:N-acetyldesloratadine