Lactone and cyclic ether analogues of platelet-activating factor. Synthesis and biological activities.
Six-membered lactone and tetrahydropyran analogues of platelet-activating factor (PAF), 4-11, and related antagonistic derivatives 41-46 were synthesized. None of the delta-lactones 4-7 showed PAF-like activities, while the corresponding cyclic ethers 8, 9 and 11 were slightly active. Some of the cyclic antagonists showed more potent inhibitory activities than the open chain antagonist CV-3988 against platelet aggregation (rabbit platelet-rich plasma, IC50) and hypotension (rat, ID50) induced by C16-PAF: e.g. dl-3-[6-[O-(trans-3-heptadecylcarbamoyloxytetrahydropyran-2- yl)methyl]phosphonoxy]hexylthiazolium (inner salt) (41d) (IC50 5.5 x 10(-7) M, ID50 0.046 mg/kg, i.v.); dl-3-[5-[O-(cis-3-heptadecylcarbamoylthiotetrahydropyran-2- yl)methyl]phosphonoxy]pentylthiazolium (inner salt) (43c) (IC50 5.7 x 10(-7) M, ID50 0.076 mg/kg, i.v.).
Miyazaki
H
H
Ohkawa
N
N
Nakamura
N
N
Ito
T
T
Sada
T
T
Oshima
T
T
Koike
H
H
D000818:Animals; D055598:Chemical Phenomena; D002621:Chemistry; D066298:In Vitro Techniques; D007783:Lactones / Q000138:chemical synthesis / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D011817:Rabbits; D051381:Rats; D011919:Rats, Inbred Strains
D007783:Lactones; D010972:Platelet Activating Factor