Renin inhibitor

Renin inhibitors are pharmaceutical drugs inhibiting the activity of renin that is responsible for hydrolyzing angiotensinogen to angiotensin I, which in turn reduces the formation of angiotensin II that facilitates blood pressure. Renin inhibitor is often preceded by direct, called direct renin inhibitor in order to distinguish its mechanism from other renin–angiotensin–aldosterone system-interfering drugs such as angiotensin converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) and aldosterone receptor antagonists. These drugs inhibit the first and rate-limiting step of the renin–angiotensin–aldosterone system (RAAS), namely the conversion of angiotensinogen to angiotensin I. This leads to a totality in absence of angiotensin II based on the rationale that renin only acts to inhibit this step unlike Angiotensin Converting Enzyme which is also involved in other biochemical reactions. Since the 1970s, scientists have been trying to develop potent inhibitors with acceptable oral bioavailability. The process was difficult and took about three decades. The first and second generations faced problems such as poor bioavailability and lack of potency. Finally, the third generation was discovered. These compounds were nonpeptidic renin inhibitors, had acceptable oral bioavailability and were potent enough for clinical use. The first drug in this class was aliskiren, which received a marketing approval in 2007. As of June 2020, it is the only renin inhibitor on the market.

History In 1896, the Finnish physiologist Robert Tigerstedt and the Swedish physician Per Bergman did an experiment on kidneys and the circulatory system in rabbits. They observed that blood pressure rose in the rabbits when extracts of the kidneys were injected into their jugular veins. They also discovered this substance responsible for higher blood pressure was produced in the renal cortex, and they named it renin. Although this experiment laid the foundation for future investigations into the RAAS pathway, it had little impact on the scientific community at that time. In 1934, when Goldblatt published his work in renal ischaemia, renin came into focus again. The importance of renin in the pathogenesis of cardiovascular disease was, however, not fully understood until in the 1970s, and 20 years later the first renin inhibitors went to clinical trials. Pepstatin, which was described in 1972, was the first synthetic renin inhibitor, but poor pharmacokinetic properties prevented it from entering in vivo investigations. The first generation of renin inhibitors, such as H-142, were peptide analogues of angiotensinogen. However, these inhibitors had also limited drug-like properties. Hopes of breakthrough appeared in 1982 when development of the second generation renin inhibitors began. This generation consisted of peptide-like compounds, such as remikiren, enalkiren and zanikiren. They had more drug-like rather than substrate-like properties, and in 1990 they went to clinical trials. The second generation had its limitations and never completed clinical trials. Aliskiren, the only renin inhibitor to go into phase III clinical trials, is not structurally related to peptides, which makes it a third-generation renin inhibitor. The first clinical trial was performed in 2000 in healthy volunteers. In 2007, aliskiren was approved by the US Food and Drug Administration and the European Medicines Agency as a treatment for hypertension. A systematic review by the Cochrane Hypertension group found the maximum recommended dose of aliskiren produced an appreciable decline in blood pressure over placebo.

The renin–angiotensin–aldosterone system

The renin–angiotensin–aldosterone system (RAAS) plays a key role in the pathology of cardiovascular disease, hypertension, diabetic kidney disease and heart failure. Under normal conditions, stimulation of the RAAS occurs in response to threats that compromise blood pressure stability, such as hypotension, blood loss and excessive loss of sodium and water. Blood pressure depends on total peripheral resistance and cardiac output. The highly selective aspartic protease renin is secreted from the juxtaglomerular apparatus, which is the only source of active renin, although its precursor, prorenin, can be secreted by other tissues, such as the salivary glands, brain, heart and blood vessels. Renin is a circulating enzyme that acts on a circulating peptide, angiotensinogen. Renin cleaves the peptide at the Leu10–Val11 bond, and this reaction is the rate-determining step of the RAAS. This leads to the product angiotensin I (Ang I) which is a decapeptide. Ang I is broken down by the angiotensin-converting enzyme (ACE) to the active octapeptide angiotensin II (Ang II), which is the principal effector of the RAAS. Ang II stimulates renal sodium retention; promotes aldosterone secretion; causes vasoconstriction, and increases sympathetic nervous system activity. Ang II also provides a negative feedback to the system by inhibiting renin release by the juxtaglomerular apparatus. Ang II interacts with at least two classes of Ang II receptors, AT1 and AT2. This mechanism, which runs from renin through Ang II and to aldosterone, as well as the negative feedback that Ang II has on renin secretion, is known as RAAS. The net effect is to increase blood pressure, which in normal physiology is necessary in order to maintain homeostasis. It is suspected that essential hypertension, a heterogeneous disorder whose long-term effects can be end organ damage, can involve at least in some cases an overactivity of this system, which several types of medications attempt to counter. Renin concentration in blood plasma tends to be higher in younger people with hypertension when vasoconstriction may be the main reason for high blood pressure. Conversely, renin is lower in older people or in people of African American or African Caribbean ethnicity when salt retention may contribute more to elevated blood pressure. However, the role of plasma renin levels in the etiology and management of hypertension is disputed.

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