Synthesis and thromboxane A2 antagonistic activity of [[1-aryl(or benzyl)-1-(benzenesulfonamido)methyl]phenyl]alkanoic acid derivatives.
In order to find new antiasthmatic and antithrombotic agents, various [[1-aryl(or benzyl)-1-(benzenesulfonamido)methyl]phenyl]alkanoic acid derivatives were synthesized. Evaluation of these compounds for thromboxane A2 (TXA2) antagonistic activities indicated that 4-[4-[(4-chlorobenzenesulfonamido)phenylmethyl]phenyl]butyric acid (6h) ,4-[4-[1-(4-chlorobenzenesulfonamido)-2-phenylethyl]phenyl]butyric acid (6y) and many other compounds have potent inhibitory effects on U-46619-induced guinea-pig platelet aggregation. No significant difference in the inhibitory effect between (+)-6h and its antipode could be detected, although (+)-6h and its antipode could be detected, although (+)-6y was about 10 times more potent than (-)6y. The pKb values of 6h and 6y were estimated to be 8.9 and 10, respectively on U-46619-induced contraction of guinea-pig trachea as a pharmacological measure of TXA2 antagonistic activity. These compounds also showed potent inhibitory effects on U-46619-induced bronchoconstriction in guinea-pig after oral administration in vivo. They were also evaluated for other related pharmacological effects involving the arachidonic acid cascade. It was found that these compounds possess TXA2 synthase inhibitory activity together with TXA2 antagonistic activity, and 6h also possesses weak leukotriene D4 (LTD4) antagonistic activity. Structure-activity relationships for TXA2 antagonistic activity of these derivatives are discussed.
Sakurai
S
S
Research and Development Division, Hokuriku Seiyaku Co., Ltd., Fukui, Japan.
Ogawa
N
N
Suzuki
T
T
Kato
K
K
Ohashi
T
T
Yasuda
S
S
Kato
H
H
Ito
Y
Y
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D000818:Animals; D018927:Anti-Asthmatic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D001792:Blood Platelets / Q000201:enzymology; D001993:Bronchodilator Agents / Q000138:chemical synthesis / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D005343:Fibrinolytic Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D017998:Leukotriene D4 / Q000037:antagonists & inhibitors / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011450:Prostaglandin Endoperoxides, Synthetic / Q000037:antagonists & inhibitors / Q000494:pharmacology; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D013928:Thromboxane A2 / Q000031:analogs & derivatives / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors; D014662:Vasoconstrictor Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology
D018927:Anti-Asthmatic Agents; D001993:Bronchodilator Agents; D005343:Fibrinolytic Agents; D010975:Platelet Aggregation Inhibitors; D011450:Prostaglandin Endoperoxides, Synthetic; D013449:Sulfonamides; D014662:Vasoconstrictor Agents; D013928:Thromboxane A2; D017998:Leukotriene D4; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D013930:Thromboxane-A Synthase