Structure-activity relationships in an imidazole-based series of thromboxane synthase inhibitors.
Analogues of 4-[[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)methoxy]methyl] ethoxy]methyl]benzoic acid (5m) were prepared and evaluated as thromboxane synthase inhibitors. A series of esters of 5m showed a parabolic relationship between lipophilicity and inhibition of TxB2 generation in intact platelets, with activities up to 50 times greater than that of dazoxiben. However, on administration to rabbits the ethyl ester 5d had a short duration of action, due to rapid metabolism and excretion via deesterification and beta-glucuronidation. Attempts at replacing the carboxylate group with other potential pharmacophores were unsuccessful.
Manley
P W
PW
Allanson
N M
NM
Booth
R F
RF
Buckle
P E
PE
Kuzniar
E J
EJ
Lad
N
N
Lai
S M
SM
Lunt
D O
DO
Tuffin
D P
DP
D000818:Animals; D001792:Blood Platelets / Q000187:drug effects / Q000201:enzymology; D002851:Chromatography, High Pressure Liquid; D003094:Collagen / Q000494:pharmacology; D011464:Epoprostenol / Q000096:biosynthesis; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D011817:Rabbits; D013329:Structure-Activity Relationship; D013928:Thromboxane A2 / Q000096:biosynthesis; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D007093:Imidazoles; D013929:Thromboxane B2; D013928:Thromboxane A2; C053318:1-(2,3-bis((4-methoxyphenyl)methoxy)propyl)-1H-imidazole; D003094:Collagen; D011464:Epoprostenol; D013930:Thromboxane-A Synthase