Benzazepinone calcium channel blockers. 2. Structure-activity and drug metabolism studies leading to potent antihypertensive agents. Comparison with benzothiazepinones.
As part of a program to discover potent antihypertensive analogues of diltiazem (3a), we prepared 1-benzazepin-2-ones (4). Benzazepinones competitively displace radiolabeled diltiazem, and show the same absolute stereochemical preferences at the calcium channel receptor protein. Derivatives of 4 containing a trifluoromethyl substituent in the fused aromatic ring show potent and long-acting antihypertensive activity. Studies of the metabolism of 4 lead to the metabolically stable antihypertensive calcium channel blockers 5a and 5c. Benzazepinone 5a is a longer acting and more potent antihypertensive agent than the second generation diltiazem analogue TA-3090 (3e).
Floyd
D M
DM
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey 08543-4000.
Kimball
S D
SD
Krapcho
J
J
Das
J
J
Turk
C F
CF
Moquin
R V
RV
Lago
M W
MW
Duff
K J
KJ
Lee
V G
VG
White
R E
RE
D000107:Acetylation; D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001552:Benzazepines / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D002121:Calcium Channel Blockers / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D004110:Diltiazem / Q000031:analogs & derivatives* / Q000737:chemistry / Q000627:therapeutic use; D006168:Guinea Pigs; D006973:Hypertension / Q000188:drug therapy; D008297:Male; D008862:Microsomes, Liver / Q000378:metabolism; D008968:Molecular Conformation; D015394:Molecular Structure; D011759:Pyrrolidines / Q000138:chemical synthesis / Q000627:therapeutic use; D011817:Rabbits; D051381:Rats; D011918:Rats, Inbred SHR; D013329:Structure-Activity Relationship; D014664:Vasodilation / Q000187:drug effects
D000959:Antihypertensive Agents; D001552:Benzazepines; D002121:Calcium Channel Blockers; D011759:Pyrrolidines; C073200:3-(acetyloxy)-1,3,4,5-tetrahydro-4-(4-methoxyphenyl)-1-(2-pyrrolidinylmethyl)-6-(trifluoromethyl)-2H-benzazepin-2-one; D004110:Diltiazem