Key result
3,4,5-Triphenyl-1H-pyrazole-1-nonanoic acid potently inhibits ADP-induced platelet aggregation at ~0.4 microM via the PGI2 receptor.
Why the study?
The structural requirements for binding to the platelet prostacyclin receptor and inhibiting ADP-induced platelet aggregation by phenylated pyrazoloalkanoic acid derivatives were not fully characterized.
Effect estimate: IC50 0.4 microM
3,4,5-Triphenyl-1H-pyrazole-1-nonanoic acid (8d) is a potent nonprostanoid prostacyclin mimetic that inhibits platelet aggregation via the PGI2 receptor.
Nonprostanoid PGI2 agonists merit in vivo thrombosis models; leaves open clinical antiplatelet utility.
A series of phenylated pyrazoloalkanoic acid derivatives were synthesized and evaluated as inhibitors of ADP-induced human platelet aggregation. 3,4,5-Triphenyl-1H-pyrazole-1-nonanoic acid (8d), with an IC50 of 0.4 microM, was the most potent inhibitor identified in this study. Biochemical studies determined that 8d increased intraplatelet cAMP accumulation and stimulated platelet membrane-bound adenylate cyclase in a concentration-dependent fashion. Displacement of [3H]iloprost by 8d from platelet membranes indicated that the platelet prostacyclin (PGI2) receptor is the locus of biological action. Structure-activity studies demonstrated that the minimum structural requirements for binding to the platelet PGI2 receptor and inhibition of ADP-induced platelet aggregation within this series are a vicinally diphenylated pyrazole substituted with an omega-alkanoic acid side chain eight or nine atoms long. Potency depended upon both side-chain length and its topological relationship with the two phenyl rings.
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Meanwell et al. (1992) studied this question. 3,4,5-Triphenyl-1H-pyrazole-1-nonanoic acid (8d) was evaluated on Inhibition of ADP-induced human platelet aggregation (IC50 0.4 microM). 3,4,5-Triphenyl-1H-pyrazole-1-nonanoic acid (8d) was identified as a potent inhibitor of ADP-induced human platelet aggregation with an IC50 of 0.4 microM, acting via the platelet PGI2 receptor.
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