Candesartan Cilexetil Atacand

Structural Formula Ball-and-Stick Model Space-filling Model

Year of discovery: 1991; Year of introduction: 1998 (AstraZeneca); Drug category: Angiotensin receptor blocker (ARB); Main uses: Treatment of hypertension and chronic heart failure; Related drugs: Eprosartan (Teveten), Losarían (Cozaar), Olmesartan (Benicar), Telmisartan (Micardis), Valsarían (Diovan).

Candesarian cilexeiil belongs to the newest class of pharmaceuticals called angiotensin receptor blockers (ARBs) that are used for the treatmenl of high blood pressure and chronic heart failure.'

Angiotensin receptor blockers, like angiotensin-converling enzyme (ACE) inhibitors, act on the renin-angiotensin syslem (RAS), which plays a major role in regulating blood pressure. The main pressor substance in the renin-angiotensin system is angiotensin II. ACE inhibitors, as discussed in the case of enalapril (see page 69), attenuate the biosynthesis of angiotensin II. Angiotensin receptor blockers affect the last step of the RAS cascade by selectively binding to, but not activating, the angiotensin II receptors, thereby blocking their interaction with angiotensin II. The result is reduction of blood pressure, as with ACE inhibition.

Although ACE inhibitors are first-line therapy in heart failure, they can cause side effects because they also inhibit the breakdown of bradykinin, which can lead to persistent dry cough in a sizeable fraction of the population (especially Asian). Angiotensin receptor blockade is an alternative for individuals intolerant of ACE inhibitor therapy. The first angiotensin receptor blocker, saralasin, was developed by scientists at Norwich Eaton. However, as this drug was a peptide, it was not orally active and was also quickly metabolized. The first non-peptide angiotensin receptor blocker, losartan, was discovered at DuPont Merck Pharmaceuticals in 1990, and introduced in 1995 under the brand name Cozaar The mosf prescribed ARB is Novartis' valsarían (Diovan), which generated more than $2.4 billion in sales in 2003. Valsarían was approved by the FDA in 1996. The competitor drug of AstraZeneca, candesarian cilexeiil, entered the market in 1998 under the brand name Atacand.

Candesarian cilexetil is a prodrug that is converted to the active drug, candesartan, during absorbtion in the gastrointestinal tract by hydrolytic cleavage of the subunit at the lower right of the above structural formula (shown in red). Candesartan binds to the angiotensin II receptor more strongly than the other members of the sartan drug family allowing the use of lower doses and minimizing side effects.2

1. Expert Opin. Pharmaco. 2004. 5. 1589-1597; 2. Am. J. Cardiol. 1999, 84, 3S-8S; Refs. p. 84

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