Sch 37370: a new drug combining antagonism of platelet-activating factor (PAF) with antagonism of histamine.
Multiple mediators are involved in the pathophysiology of allergic and inflammatory disorders. Drugs that affect the action of more than one mediator may, therefore, be particularly effective in these disorders. Two such mediators are platelet-activating factor (PAF) and histamine. From a structural series with documented antihistamine activity, Sch 37370 has been identified as a dual antagonist of PAF and histamine. In vitro, Sch 37370 selectively inhibits PAF-induced aggregation of human platelets (IC50 = 0.6 microM) and also competes with PAF binding to specific sites in membrane preparations from human lungs (IC50 = 1.2 microM). Sch 37370 also blocks the binding of [3H]pyrilamine to histamine H1 receptors in rat brain membranes. In guinea pigs, orally administered Sch 37370 is effective against bronchospasm to histamine (ED50 = 2.4 mg/kg), PAF (ED50 = 6.0 mg/kg) or serotonin (ED50 = 9.6 mg/kg). In contrast, it only weakly antagonizes methacholine-induced bronchospasm (ED50 = 51 mg/kg) and is totally inactive at 50 mg/kg against bronchospasm due to leukotriene C4 or substance P. Sch 37370 blocks hypotension in rats and a cutaneous reaction in monkeys induced by either PAF or histamine, as well as PAF-induced edema in the rat pleural cavity. In addition, Sch 37370 blocks bronchospasm induced by either antigen in sensitized guinea pigs or hyperventilation in nonsensitized guinea pigs. Sch 37370 also inhibits antigen-induced lung eosinophilia in sensitized guinea pigs and a reverse passive Arthus reaction in rats. Although Sch 37370 is not the most potent PAF antagonist or antihistamine, it is the first compound that combines these pharmacologically relevant activities and may offer important advantages over currently available antihistamine therapies.
Billah
M M
MM
Department of Allergy and Immunology, Schering-Plough Research, Bloomfield, New Jersey 07003.
Chapman
R W
RW
Watnick
A S
AS
Egan
R W
RW
Siegel
M I
MI
Kreutner
W
W
D000818:Animals; D000941:Antigens / Q000276:immunology; D001986:Bronchial Spasm / Q000139:chemically induced / Q000209:etiology / Q000503:physiopathology; D006168:Guinea Pigs; D006633:Histamine Antagonists / Q000494:pharmacology*; D006801:Humans; D006985:Hyperventilation / Q000150:complications; D017336:Loratadine / Q000031:analogs & derivatives; D008297:Male; D010880:Piperidines / Q000737:chemistry / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew
D000941:Antigens; D006633:Histamine Antagonists; D010880:Piperidines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D017336:Loratadine; C063524:N-acetyldesloratadine