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 nonpeptide AII receptor antagonists, benzimidazole-7-carboxylic acids including candesartan. Candesartan is a highly potent and insurmountable angiotensin II 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. The benzimidazole ring was found to be one of the most suitable templates arranging these three essential components in correct direction. Especially, the presence of a carboxyl group at the 7-position was found to be essential for insurmountable antagonism. Although candesartan is a very potent AII antagonist, it was found to be absorbed rather inefficiently upon oral administration. To improve bioavailability (BA) of candesartan, chemical modification was examined to yield candesartan cilexetil, a prodrug of candesartan. Candesartan cilexetil is a potent and long-acting blocker that provides effective 24 hr blood pressure control. Our alternative research efforts to improve oral BA was performed by replacement of the tetrazole ring in candesartan by other new acidic bioisosteric heterocyclic rings to find the nonprodrug AII antagonist TAK-536, bearing 5-oxo-1,2,4-oxadiazole ring, which was as potent and orally active as candesartan cilexetil.