Takehiko Naka

A new class of angiotensin II receptor antagonists with a novel acidic bioisostere

Abstract The synthesis and angiotensin II (AII) antagonistic activity of 2-substituted benzimidazole-7-carboxylic acids ( 8 ) bearing a novel acidic bioisostere, a 5-oxo-1,2,4-oxadiazole ring, are described. These compounds had in vitro and in vivo AII receptor antagonistic activity comparable to that of tetrazole analogs. The representative compound, TAK-536 ( 8e ) is a potent, orally active and specific AII receptor antagonist.

A NEW CLASS OF DIACIDIC NONPEPTIDE ANGIOTENSIN II RECEPTOR ANTAGONISTS

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.