BM-520, an original TXA2 modulator, inhibits the action of thromboxane A2 and 8-iso-prostaglandin F2alphain vitro and in vivo on human and rodent platelets, and aortic vascular smooth muscles from rodents.
Thromboxane A(2) (TXA(2)) and 8-iso-PGF(2alpha) are two prostanoid agonists of the thromboxane A(2) receptor (TP), whose activation has been involved in platelet aggregation and atherosclerosis. Agents able to counteract the actions of these agonists are of great interest in the treatment and prevention of cardiovascular events. Here, we investigated in vitro and in vivo the pharmacological profile of BM-520, a new TP antagonist. In our experiments, this compound showed a great binding affinity for human washed platelets TP receptors, and prevented human platelet activation and aggregation induced by U-46619, arachidonic acid and 8-iso-PGF(2alpha). The TP receptor antagonist property of BM-520 was confirmed by its relaxing effect on rat aorta smooth muscle preparations precontracted with U-46619 and 8-iso-PGF(2alpha). Further, its TP antagonism was also demonstrated in vivo in guinea pig after a single intravenous injection (10 mg kg(-1)). We conclude that this novel TP antagonist could be a promising therapeutic tool in pathologies such as atherosclerosis where an increased production of TXA(2) and 8-iso-PGF(2alpha), as well as TP activation are well-established pathogenic events.
Rolin
S
S
Department of Pharmacy, University of Namur, Rue de Bruxelles, 61, B-5000 Namur, Belgium.
Hanson
J
J
Vastersaegher
C
C
Cherdon
C
C
Pratico
D
D
Masereel
B
B
Dogne
J M
JM
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000737:chemistry; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism*; D001792:Blood Platelets / Q000378:metabolism; D019086:Bridged Bicyclo Compounds, Heterocyclic; D015237:Dinoprost / Q000031:analogs & derivatives* / Q000737:chemistry; D004159:Diphenylamine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated; D006168:Guinea Pigs; D006801:Humans; D006834:Hydrazines / Q000737:chemistry; D008297:Male; D008956:Models, Chemical; D009131:Muscle, Smooth, Vascular / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013453:Sulfonylurea Compounds / Q000737:chemistry* / Q000494:pharmacology; D013928:Thromboxane A2 / Q000378:metabolism*
D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006834:Hydrazines; C475768:N-terbutyl-N'-(2-(4'-methylphenylamino)-5-nitrobenzenesulfonyl)urea; C523185:N-tert-butyl-N'-(2-(3-'-methylphenylamino)-5-nitrobenzenesulfonyl)urea; D013453:Sulfonylurea Compounds; C075750:8-epi-prostaglandin F2alpha; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C045749:SQ 29548; D004159:Diphenylamine; D015237:Dinoprost