Thromboxane synthetase inhibitors and antihypertensive agents. 4. N-[(1H-imidazol-1-yl)alkyl] derivatives of quinazoline-2,4(1H,3H)-diones, quinazolin-4(3H)-ones, and 1,2,3-benzotriazin-4(3H)-ones.
The quinazolinedione, quinazolinone, and 1,2,3-benzotriazinone title compounds were prepared as analogues of N-[(1H-imidazol-1-yl)alkyl]-1H-isoindole-1,3(2H)-diones which were the subject of a previous report from our laboratories. These compounds were evaluated as thromboxane (TX) synthetase inhibitors and as antihypertensive agents. While each series of compounds had activity both as TX synthetase inhibitors and as antihypertensives, the best compounds were N-[(1H-imidazol-1-yl)alkyl]quinazoline-2,4(1H,3H]-diones (V). In general these compounds were all selective enzyme inhibitors at least equipotent with the standard dazoxiben. These compounds were also very active antihypertensive agents as determined in SHR. The SAR is discussed for both types of activity. Compound 20a was further evaluated for TX formation inhibiting properties in several other platelet types both in vitro and ex vivo and is between 100 and 1000 times more potent than dazoxiben.
Wright
W B
WB
CNS-Cardiovascular Disease Research Section, Medical Research Division of American Cyanamid Company, Lederle Laboratories, Pearl River, New York 10965.
Tomcufcik
A S
AS
Chan
P S
PS
Marsico
J W
JW
Press
J B
JB
D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D006801:Humans; D008297:Male; D011799:Quinazolines / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*
D000959:Antihypertensive Agents; D011799:Quinazolines; D013930:Thromboxane-A Synthase