Biochemical and pharmacological properties of SR 27388, a dual antioxidant and PAF receptor antagonist.
SR 27388 (N-(2-dimethylaminoethyl)-N-(3-pyridinylmethyl[4-(3,5-di(tert- butyl)-4-hydroxylphenyl)thiazol-2-yl]amine) is a potent and competitive antagonist of the binding of [3H]PAF to its receptor on rabbit platelets exhibiting an equilibrium inhibition constant for PAF binding of 10.5 +/- 1.2 nM (n = 3). SR 27388 potently inhibited PAF-induced aggregation of rabbit platelets in vitro (IC50 = 65 +/- 12 nM) (n = 4). In this respect, SR 27388 was as potent as the triazolothienodiazepine WEB-2086 against PAF-induced aggregation of rabbit platelets and had no effect on the action of other platelet aggregating agents. SR 27388 prevented in a dose-dependent manner the formation of thiobarbituric acid reactive substances during membrane peroxidation (IC50 = 0.7 microM) and inhibited reduction of the stable 1,1-diphenyl-2-picrylhydrazyl radical, indicating that the antioxidant potency of SR 27388 was due to an efficient radical scavenging activity. SR 27388 displayed marked in vitro inhibition of zymosan-induced oxidative burst in human monuclear cells (IC50 = 3 microM). In vivo, SR 27388 protected mice from 100 micrograms/kg PAF-induced death with an ED50 value of 500 micrograms/kg, when given i.v., 5 min before PAF challenge or p.o. (ED50 = 800 micrograms/kg) when given 1 h before PAF administration. Similarly, i.v. or oral doses of SR 27388 afforded in mice complete protection against endotoxin-induced lethality (ED50 values were 250 micrograms/kg and 1.3 mg/kg, respectively). Neither BHT, vitamin E nor catechin exhibited significant protection against PAF- or endotoxin-induced death. In ovalbumin-presensitized rabbits, SR 27388 premixed with the allergen inhibited in a dose-dependent manner allergen-induced oedema formation in the skin (ED50 = 0.1 mumol/site). After an i.v. administration of 10 mg/kg, SR 27388 significantly protected mice against alloxan-induced diabetes. These results show that SR 27388 is a potent and orally active dual PAF receptor antagonist and antioxidant.
Herbert
J M
JM
Sanofi Recherche, Toulouse, France.
Fraisse
L
L
Bachy
A
A
Valette
G
G
Savi
P
P
Laplace
M C
MC
Lassalle
J
J
Roche
B
B
Lale
A
A
Keane
P E
PE
D000818:Animals; D000975:Antioxidants / Q000494:pharmacology*; D001381:Azepines / Q000494:pharmacology; D001786:Blood Glucose / Q000187:drug effects; D001792:Blood Platelets / Q000378:metabolism*; D002417:Cattle; D003921:Diabetes Mellitus, Experimental / Q000097:blood; D016166:Free Radical Scavengers; D006801:Humans; D015227:Lipid Peroxidation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism*; D009000:Monocytes / Q000187:drug effects / Q000378:metabolism*; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011817:Rabbits; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D012772:Shock, Septic / Q000503:physiopathology; D013481:Superoxides / Q000097:blood; D013566:Sympathomimetics / Q000009:adverse effects*; D013844:Thiazoles / Q000494:pharmacology* / Q000633:toxicity; D017392:Thiobarbituric Acid Reactive Substances / Q000032:analysis; D014230:Triazoles / Q000494:pharmacology
D000975:Antioxidants; D001381:Azepines; D001786:Blood Glucose; D016166:Free Radical Scavengers; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013566:Sympathomimetics; D013844:Thiazoles; D017392:Thiobarbituric Acid Reactive Substances; D014230:Triazoles; C039351:platelet activating factor receptor; C052518:WEB 2086; D013481:Superoxides; C084836:SR 27388