Biochemical and pharmacological activity of arene-fused prostacyclin analogues on human platelets.
Human platelets have been employed as an assay system to evaluate the pharmacological activity of a group of stable, arene-fused prostacyclin analogs. Prostacyclin (PGI2) is a highly active member of the eicosanoid family and is relatively unstable under physiological conditions. Prostacyclin's best characterized activities are those of inhibition of platelet aggregation and relaxation of vascular smooth muscle. These activities are mediated in large part via elevation of intracellular levels of cyclic AMP subsequent to receptor occupation and activation of adenylate cyclase. We previously described the synthesis of a series of arene-fused prostacyclin analogs with stability in aqueous media at physiological pH. Several of these compounds have prostacyclin-like activities, i.e., competitive binding at the platelet prostacyclin receptor, elevation of intraplatelet cyclic AMP levels and inhibition of human platelet aggregation. One compound in particular (11a) demonstrated these activities with potency similar to PGI2, i.e., Kd at platelet receptor of 3.7 nM and IC50 for inhibition of collagen-induced human platelet aggregation in plasma of 2.9 nM.
Lilly Research Laboratories, Eli Lilly & Co., Indianapolis, IN 46208-0821.
J A
JA
Jakubowski
B G
BG
Utterback
D E
DE
Mais
S A
SA
Hardinger
T F
TF
Braish
C R
CR
Nevill
P L
PL
Fuchs
D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism; D011464:Epoprostenol / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology*; D006801:Humans; D066298:In Vitro Techniques; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin / Q000378:metabolism; D014665:Vasodilator Agents / Q000494:pharmacology*
D010975:Platelet Aggregation Inhibitors; D044006:Receptors, Epoprostenol; D011982:Receptors, Prostaglandin; D014665:Vasodilator Agents; D011464:Epoprostenol; D000242:Cyclic AMP