Structure-activity relationship in PAF-acether. 4. Synthesis and biological activities of carboxylate isosteres.
The synthesis and biological characterization of some 3-carboxylate isosteres of PAF-acether structurally modified in positions 1 (ether, carbamate), 2 (acetoyl, ethoxy), and 3 (chain length and polar head group) are reported. All derivatives present antagonist activities against PAF-acether-induced effects in vitro (platelet aggregation) and in vivo (bronchoconstriction and thrombocytopenia in guinea pig and, to a lesser extent, hypotension in rat). The functional modifications presented here do not modify dramatically the potency of antagonist activities, and there is no enantioselectivity. All of the isosteres are specific PAF-acether antagonists, except the 1-carbamoyl analogue, which is also potent against acetylcholine-induced hypotension and bronchoconstriction.
Wichrowski
B
B
Laboratoire de Pharmacochimie Moléculaire, Université Paris, France.
Jouquey
S
S
Broquet
C
C
Heymans
F
F
Godfroid
J J
JJ
Fichelle
J
J
Worcel
M
M
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001980:Bronchi / Q000187:drug effects; D006168:Guinea Pigs; D066298:In Vitro Techniques; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000138:chemical synthesis; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D011919:Rats, Inbred Strains; D013329:Structure-Activity Relationship
D010972:Platelet Activating Factor