Thromboxane synthase inhibitors. Synthesis and pharmacological activity of (R)-, (S)-, and (+/-)-2,2-dimethyl-6-[2-(1H-imidazol-1-yl)-1-[[(4-methoxyphenyl)- methoxy]methyl]ethoxy]hexanoic acids.
A series of substituted omega-[2-(1H-imidazol-1-yl)ethoxy]alkanoic acid derivatives were synthesized and evaluated for their ability to inhibit thromboxane synthase both in vitro and in vivo. Compound 13 was identified as a potent and selective competitive inhibitor of human platelet thromboxane synthase having a Ki value of 9.6 X 10(-8) M. In collagen-treated human whole blood, 13 potentiated levels of 6-keto PGF1 alpha. Enantiospecific syntheses afforded the R and S enantiomers of 13, of which the S enantiomer 13b was the more potent. Compounds 13 and 13b were potent in vivo inhibitors of thromboxane synthase with good oral activity and duration of action.
Manley
P W
PW
Department of Biology, Searle Research and Development, Division of G. D. Searle & Co. Ltd., Buckinghamshire, U.K.
Tuffin
D P
DP
Allanson
N M
NM
Buckle
P E
PE
Lad
N
N
Lai
S M
SM
Lunt
D O
DO
Porter
R A
RA
Wade
P J
PJ
D015121:6-Ketoprostaglandin F1 alpha / Q000097:blood; D000284:Administration, Oral; D000818:Animals; D002208:Caproates / Q000138:chemical synthesis* / Q000494:pharmacology; D003094:Collagen / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D007093:Imidazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D007700:Kinetics; D011450:Prostaglandin Endoperoxides, Synthetic / Q000378:metabolism; D044262:Prostaglandin H2; D011463:Prostaglandins H / Q000378:metabolism; D013237:Stereoisomerism; D013929:Thromboxane B2 / Q000097:blood; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D002208:Caproates; D004791:Enzyme Inhibitors; D007093:Imidazoles; D011450:Prostaglandin Endoperoxides, Synthetic; D011463:Prostaglandins H; D044262:Prostaglandin H2; D013929:Thromboxane B2; D015121:6-Ketoprostaglandin F1 alpha; D003094:Collagen; D013930:Thromboxane-A Synthase