Quinones. 4. Novel eicosanoid antagonists: Synthesis and pharmacological evaluation

Article abstract of DOI:10.1021/jm00129a030

A new series of ω-phenyl-ω-quinonylalkanoic acids and related compounds was synthesized. The compounds were tested for their inhibitory effects on U-44069-induced contraction of the rabbit aorta. (±)-7-(3,5,6-Trimethyl-1,4-benzoquinon-2-yl)-7-phenylheptanoic acid (4d) (AA-2414) with pA₂ value of 8.28 was one of the most potent compounds. Compound 4d inhibited U-46619-induced contraction of the guinea pig lung (pA₂ = 8.29) and U-44069-induced aggregation of the guinea pig platelet (IC₅₀ = 3.5 x 10^-7 M). Compound 4d displaced the binding of [³H]U-46619 to guinea pig platelets (IC₅₀ = 7.4 x 10^-9 M). Compound 4d also showed very potent inhibitory effects with an MED of 0.3 mg/kg (po) on U-46619-, LTD₄-, PAF-, or IgG₁-induced bronchoconstriction in guinea pigs. The enantiomers of 4d were prepared. The R-(+) isomer 8a was active in both in vitro and in vivo tests, but the S-(-) isomer 8b was much less active. We concluded that the antiasthmatic effects of 4d were based mainly on the TXA₂ receptor antagonistic action. In addition, compound 4d showed potent inhibitory effects on PGD₂-, PGF(2α)-, and 11-epi-PGF(2α)-induced contraction of the guinea pig tracheal strips. The diverse inhibitory effects might be expressed in terms of eicosanoid-antagonistic activity.