title: Biological effects of the new platelet-activating factor receptor antagonist (+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one hydrochloride.
abstract: SM-12502 ((+)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one HCl, CAS 119383-00-5) inhibited platelet-activating factor (PAF)-induced aggregation of rabbit and human platelets with IC50 values of 2.3 mumol/l and 4.7 mumol/l, respectively, but did not inhibit platelet aggregation induced by adenosine diphosphate, collagen, thrombin, arachidonic acid, U46619 (a thromboxane A2 agonist) or Ca2+ ionophore A23187 at concentrations up to 400 mumol/l. SM-12502 competitively antagonized 3H-PAF binding to rabbit platelets with an IC50 of 1.0 mumol/l. In contrast, the anti-PAF activity of the optical isomer SM-12501 ((-)-cis-3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one HCl) was much weaker and its IC50 was more than 100 mumol/l. SM-12502 prevented PAF-induced death in mice with ID50 values of 4.8 mg/kg (i.v.) or 68.6 mg/kg (p.o.). In guinea pigs, SM-12502 inhibited PAF (0.1 micrograms/kg)-induced hemoconcentration with ID50 values of 1.9 mg/kg (i.v.) or 40.2 mg/kg (p.o.). In addition, SM-12502 inhibited PAF (10 ng/kg)-induced hypotension in rats with ID50 values of 2.0 mg/kg (i.v.) or 6.5 mg/kg (p.o.). The in vivo effects of SM-12501 were much weaker. Orally administered SM-12502 showed rapid absorption and a long duration of pharmacological activity in rats. SM-12502 afforded dose-dependent protection against anaphylactic death in mice with ID50 values of 18.4 mg/kg (i.v.) and 136 mg/kg (p.o.). It also inhibited endotoxin (E. coli 0.55:B5, 60 mg/kg)-induced death in mice, with ID50 values of 119 mg/kg (i.v.) and 182 mg/kg (p.o.).(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Research Laboratories, Sumitomto Pharmaceuticals Co., Ltd., Osaka, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Imanishi
authors.forename: M
authors.initials: M
authors.lastname: Murakami-Uchida
authors.forename: H
authors.initials: H
authors.lastname: Koike
authors.forename: Y
authors.initials: Y
authors.lastname: Natsume
authors.forename: S
authors.initials: S
authors.lastname: Morooka
mesh_terms: D000707:Anaphylaxis / Q000517:prevention & control; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D001794:Blood Pressure / Q000187:drug effects; D004731:Endotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000633:toxicity; D010974:Platelet Aggregation / Q000187:drug effects; D010980:Platelet Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D011817:Rabbits; D051381:Rats; D017208:Rats, Wistar; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013237:Stereoisomerism; D013844:Thiazoles / Q000494:pharmacology*; D053778:Thiazolidines
chemical_list: D004731:Endotoxins; D010972:Platelet Activating Factor; D010980:Platelet Membrane Glycoproteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D013844:Thiazoles; D053778:Thiazolidines; C039351:platelet activating factor receptor; C065776:3,5-dimethyl-2-(3-pyridyl)thiazolidin-4-one