The discovery of clinically useful nonpeptide antagonists of Ang II led to the recognition of the importance of this hormone in the control of circulation and to a new approach to the treatment of hypertension. Although at least four different types of Ang II receptors (AT1-4) have been identified, pressor and other undesirable effects of Ang II are mediated by AT1 receptors. Furukawa et al. from Takeda Chemical Industries initially described the antagonism of Ang II by N-benzylimidazole derivatives. Intensive structure-activity and optimization studies at DuPont Merck Pharmaceutical Company led to the discovery and development of the first marketed ARB, losartan (Table 6). Its discovery was followed by the development of a series of chemically related compounds, known as 'sartans.' Losartan and other 'sartans' block vasoconstrictor, aldosterone-releasing, and adrenergic-facilitating effects of Ang II. Losartan is converted in the liver to two carboxylic acid derivatives that are substantially more potent than the parent compound. Losartan and other ARBs lower arterial pressure in renal hypertensive (2K1C) and SHR. They also lower blood pressure in sodium-depleted normotensive animals. Unlike ACEIs, Ang II antagonists do not inhibit bradykinin breakdown and, therefore, do not produce cough. Also, selective AT1 antagonists do not interfere with the activation of AT2 by Ang II. This is likely to be beneficial, since AT2 receptors are thought to oppose the actions of Ang II at AT1 receptors. Another conceivable advantage of ARBs, compared to ACEIs, is the existence of non-ACE pathways for synthesis of Ang II, so that ACEIs cannot be expected to prevent the formation of Ang II completely.
Valsartan has no active metabolites, it is less potent, but its elimination half-life is longer than that of losartan. Irbesartan has better bioavailability and is more likely to enter the brain than either losartan or valsartan.39
Table 6 Chemical structures, elimination half-lives (f1/2), and bioavailabilities of marketed angiotensin II antagonists (ARBs)
Elimination half-life, tip (h) Bioavailability (%)
ch2 I 2 ch2
I 2 CH3
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