[Angiotensin II receptor antagonists: candesartan cilexetil].
Blockade of the action of angiotensin II (AII) has long been a target for the development of novel antihypertensive agents. We recently discovered a novel class of potent nonpeptide AII receptor antagonists, benzimidazole-7-carboxylic acids including candesartan. Candesartan is a highly potent and insurmountable AII type-1 receptor (AT1)-selective antagonist. Structure-activity relationship (SAR) studies revealed that the adjacent arrangement of a lipophilic substituent, a tetrazolylbiphenylmethyl moiety and a carboxyl group was the important structural requirement for potent AII antagonistic activity. Especially, the presence of a carboxyl group at the 7-position was found to be essential for insurmountable antagonism. To improve bioavailability of candesartan, chemical modification was examined to yield candesartan cilexetil, a prodrug of candesartan. Candesartan cilexetil is a potent and long-acting blocker that, when given once a day to patients, provides effective 24 hr blood pressure control.
Naka
T
T
Medicinal Chemistry Research Laboratories, Takeda Chemical Industries, Ltd., 2-17-85 Jusohonmachi, Yodogawa-ku, Osaka 532-8686, Japan.
Kubo
K
K
Nishikawa
K
K
Inada
Y
Y
Furukawa
Y
Y
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000737:chemistry; D001713:Biphenyl Compounds / Q000138:chemical synthesis / Q000737:chemistry; D002986:Clinical Trials as Topic; D004195:Disease Models, Animal; D017277:Drug Approval; D006333:Heart Failure / Q000188:drug therapy; D006801:Humans; D006973:Hypertension / Q000188:drug therapy; D066298:In Vitro Techniques; D007674:Kidney Diseases / Q000188:drug therapy; D020521:Stroke / Q000517:prevention & control; D013329:Structure-Activity Relationship; D013777:Tetrazoles
D057911:Angiotensin Receptor Antagonists; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; C077793:candesartan cilexetil