Direct renin inhibitors (DRIs) are the first new class of drugs in 14 years that are available for the treatment of hypertension. Cleavage of angiotensinogen to angiotensin I by renin is the initial rate-limiting step of the renin–angiotensin system (RAS) and has long been recognised as a preferred site for blockade of RAS.1 Angiotensin-converting enzyme inhibitors (ACEIs) work a step later, preventing the conversion of angiotensin I to angiotensin II. Angiotensin receptor blockers (ARBs) block the final step, which is the binding of angiotensin II to the angiotensin II type 1 (AT1) receptor (see Figure 1). There exist several limitations in the efficacy of RAS blockage with the current RAS inhibitors ACEIs and ARBs. Non-ACE pathways can be activated under an ACE-inhibited situation in some organs, such as the kidneys, heart and blood vessels, and angiotensin II generation may continue (angiotensin II escape).2,3 Under an AT1 receptor-inhibited condition, higher levels of circulating angiotensin II, which is not only a potent vasoconstrictor but also a generator of various growth-promoting pro-inflammatory cytokines, fibrosis and oxygen radical mediators, may bring about a harmful effect on the cardiovascular system.4 Only beta-blockers have been known to lower the secretion rate of renin from the kidneys to reduce its plasma concentration, as well as plasma renin activity (PRA). However, there is little evidence suggesting end-organ protection effects by RAS blockade with beta-blockers. In contrast, DRIs bind to the active site of the renin molecule blocking angiotensinogen cleavage, thus preventing the formation of angiotensin I.1 Blockade of the RAS at any point leads to a compensatory increase in renin release, as angiotensin II levels drop or its effects at AT1 receptors on juxtaglomerular cells in the kidney are blocked. However, DRIs are unique in counteracting the resultant increase in circulating renin concentration by inhibiting its action as an enzyme, i.e. reducing PRA.5 Of course, long-term outcome evaluation study is warranted to exclude concerns related to the elevation of plasma renin.6 However, initial results with DRIs have shown superior RAS blocking efficacy to beta-blockers and at least the same range as ACEIs or ARBs.7
Although a number of DRIs, such as ditekiren, enalkiren, zankiren and remikiren, have been synthesised in the past, they were not developed for clinical use due to poor oral bioavailability, low efficacy, short half-life and high cost of synthesis.5 However, by means of crystallography and computational molecular modelling, the orally active compound aliskiren was discovered.1,8,9
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