Design, synthesis, and pharmacology of 3-substituted sodium azulene-1-sulfonates and related compounds: non-prostanoid thromboxane A2 receptor antagonists.
A series of novel azulene-1 carboxylic acid derivatives 28-30, azulene-1 sulfonic acid sodium salts 41a-c, and related compounds were synthesized. These compounds were tested for TXA2 receptor antagonistic activity. The inhibitory concentrations (IC50) of these compounds for vascular contraction (TXA2 tau receptor) and platelet aggregation (TXA2 alpha receptor) induced by (15S)-15-hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5(Z),13(E)- dienoic acid (U-46619) were obtained. Azulene-1-sulfonic acid sodium salts 41a-c were over 3 times more potent than azulene-1-carboxylic acids 28-30. The most potent compound, 41b was 4 orders of magnitude more potent than a TXA2 antagonist, BM13,177, in inhibiting vascular contraction (tau receptor) and had an IC50 of 9.0 x 10(-10) M. Compound 41b was also found to be a tau receptor selective antagonist (IC50 of contraction/IC50 of aggregation = 378) and to have no TXA2 synthetase inhibitory activity at concentrations up to 10(-4) M and no partial agonistic activity at concentrations up to 10(-5) M in rabbit aorta (tau receptor) and up to 10(-4) M in rabbit platelet-rich plasma (alpha receptor). In a radioligand binding assay using rabbit gel-filtered platelets, compound 41b had a high-affinity binding for the TXA2 receptor. In an in vivo study, compound 41b inhibited U-46619-induced sudden death in mice at a dose of 0.3 mg/kg and its duration of action was over 8 h when administered orally at 3 mg/kg.
Tomiyama
T
T
Kotobuki Research Laboratories, Kotobuki Seiyaku Company, Ltd., Nagano, Japan.
Yokota
M
M
Wakabayashi
S
S
Kosakai
K
K
Yanagisawa
T
T
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D003508:Cycloheptanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008297:Male; D051379:Mice; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors / Q000633:toxicity; D011817:Rabbits; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013928:Thromboxane A2 / Q000037:antagonists & inhibitors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000633:toxicity
D003508:Cycloheptanes; D011450:Prostaglandin Endoperoxides, Synthetic; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D013928:Thromboxane A2; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid