A new class of diacidic nonpeptide angiotensin II receptor antagonists: candesartan cilexetil.
Blockade of the action of angiotensin ii (AII) has long been a target for development of novel antihypertensive agents. We recently discovered a novel class of potent non-peptide AII receptor antagonists, benzimidazole-7-carboxylic acids including candesartan. Candesartan is a highly potent and insurmountable antagonist selective in the angiotensin II type-I receptor (AT1). 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-daily to patients, provides effective 24 hr blood pressure control.
Naka
T
T
Pharmaceutical Research Division, Takeda Chemical Industries, Ltd., Osaka, Japan.
Kubo
K
K
Inada
Y
Y
Nishikawa
K
K
D000804:Angiotensin II / Q000037:antagonists & inhibitors*; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology; D001562:Benzimidazoles / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D001667:Binding, Competitive; D001682:Biological Availability; D001713:Biphenyl Compounds / Q000008:administration & dosage* / Q000737:chemistry / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D002986:Clinical Trials as Topic; D004305:Dose-Response Relationship, Drug; D006801:Humans; D013329:Structure-Activity Relationship; D013777:Tetrazoles / Q000737:chemistry; D013997:Time Factors
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D013777:Tetrazoles; D000804:Angiotensin II; C077793:candesartan cilexetil