Quinones. 4. Novel eicosanoid antagonists: synthesis and pharmacological evaluation.
A new series of omega-phenyl-omega-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-, PGF2 alpha-, and 11-epi-PGF2 alpha-induced contraction of the guinea pig tracheal strips. The diverse inhibitory effects might be expressed in terms of eicosanoid-antagonistic activity.
Shiraishi
M
M
Central Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Kato
K
K
Terao
S
S
Ashida
Y
Y
Terashita
Z
Z
Kito
G
G
D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors*; D001249:Asthma / Q000503:physiopathology; D016227:Benzoquinones; D001980:Bronchi / Q000187:drug effects; D001985:Bronchial Provocation Tests; D055598:Chemical Phenomena; D002621:Chemistry; D006168:Guinea Pigs; D006538:Heptanoic Acids; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors; D011809:Quinones / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D013189:SRS-A / Q000037:antagonists & inhibitors; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014132:Trachea
D001095:Arachidonic Acids; D016227:Benzoquinones; D006538:Heptanoic Acids; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D011809:Quinones; D013189:SRS-A; C060230:seratrodast; C028429:U 44069