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.