Synthesis of [[(benzenesulfonamido)alkyl]phenyl]alkanoic acid derivatives containing pyridyl or imidazolyl groups and their thromboxane A2 receptor antagonistic and thromboxane A2 synthase inhibitory activities.
As part of our search for a dual inhibitor possessing both thromboxane A2 (TXA2) receptor antagonistic and TXA2 synthase inhibitory activities, some [[(benzenesulfonamido)alkyl]phenyl]alkanoic acid derivatives possessing a pyridyl or imidazolyl group were synthesized. Their TXA2 receptor antagonistic and TXA2 synthase inhibitory activities were evaluated in terms of the inhibitory effects on U-46619-induced guinea-pig platelet aggregation and on thromboxane B2 (TXB2) production in human platelets, respectively. It was found that 3-[4-[2-(1-imidazolyl)-1-(4-chlorobenzenesulfonamido)ethyl]phenyl] propionic acid (22a), containing an imidazolyl group, is a well-balanced dual inhibitor having both TXA2 receptor antagonistic activity (IC50 = 0.31 microM) and TXA2 synthase inhibitory activity (IC50 = 0.39 microM).
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
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002264:Carboxylic Acids / Q000138:chemical synthesis* / Q000494:pharmacology; D055598:Chemical Phenomena; D002627:Chemistry, Physical; D006168:Guinea Pigs; D006801:Humans; D066298:In Vitro Techniques; D009682:Magnetic Resonance Spectroscopy; D008968:Molecular Conformation; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000494:pharmacology; D013929:Thromboxane B2 / Q000096:biosynthesis / Q000378:metabolism*; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D002264:Carboxylic Acids; D010975:Platelet Aggregation Inhibitors; D017482:Receptors, Thromboxane; D013449:Sulfonamides; D013929:Thromboxane B2; D013930:Thromboxane-A Synthase