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. , 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.
Mechanism of action Renin inhibitors bind to the active site of renin and inhibit the binding of renin to angiotensinogen, which is the rate-determining step of the RAAS cascade. Consequently, renin inhibitors prevent the formation of Ang I and Ang II. Renin inhibitors may also prevent Ang-(1-7), Ang-(1-9) and Ang-(1-5) formation, although it is not known if this is clinically important. Renin is highly selective for its only naturally occurring substrate which is angiotensinogen, and the incidence of unwanted side effects with a renin inhibitor is infrequent. and similar to angiotensin II receptor antagonists. Ang II also functions within the RAAS as a negative feedback to suppress further release of renin. A reduction in Ang II levels or blockade of angiotensin receptors will suppress the feedback loop and lead to increased plasma renin concentrations (PRC) and plasma renin activity (PRA). This can be problematic for ACE inhibitor and angiotensin II receptor antagonist therapy since increased PRA could partially overcome the pharmacologic inhibition of the RAAS cascade. Because renin inhibitors directly affect renin activity, decrease of PRA despite the increased PRC (from loss of the negative feedback) may be clinically advantageous.
Drug discovery and development
Pepstatin – the first renin inhibitor Pepstatin was the first synthetic renin inhibitor. It is of microbial origin and is an N-acyl-pentapeptide, more accurately: isovaleryl-L-valyl-L-valyl-statyl-L-alanyl-statine. Pepstatin was found to be a potent competitive inhibitor of most aspartic proteases, but a weak inhibitor of renin. Originally, it was thought to be effective in the treatment of duodenal ulcers, and went through clinical trials, but had no success. Statine, an amino acid, is thought to be responsible for the inhibitory activity of pepstatin, because it mimics the tetrahedral transition state of the peptide catalysis. Because of hydrophobic properties of statine, pepstatin has very low solubility in physiological media. Since it had low potency and poor solubility, it did not enter in vivo studies.
First generation: peptide analogues
This generation consists of two groups of compounds, either peptide analogues of the prosegment of renin or peptide analogues of the amino-terminal part of the substrate angiotensinogen. The drugs in the latter group seemed to be effective in inhibiting renin activity and lowering blood pressure in both animals and humans. Unfortunately, they had to be given parenterally because of poor bioavailability. They also turned out to have short durations of action, low potencies and their ability to lower blood pressure was inadequate. None of these drugs completed clinical investigations.
Second generation: peptide mimetics
Compounds in this generation were more potent, more stable and had longer durations of action. One of these, CGP2928, a peptidomimetic compound, was the first renin inhibitor proven effective when taken orally. Tested on marmosets, it was only active at high doses. Development of new drugs in the second generation continued to improve pharmacokinetic properties. Remikiren, enalkiren and zankiren were then discovered. These were peptidomimetic inhibitors with improved structures that made them more specific, potent and stable. Unfortunately, clinical development was terminated because the drugs had poor oral bioavailability (poorly absorbed and rapidly metabolized) and lowering blood pressure activity still remained low.
Third generation: non-peptides
Aliskiren, an orally active non-peptide renin inhibitor, was the first drug in its class on the market. It is used to treat hypertension as monotherapy or in combination with other antihypertensive agents. The key to the discovery of aliskiren was crystallography and molecular modeling techniques. Now, a solution has been found to the problem that impeded the development of the renin inhibitors of the previous generations. Non-peptide substances were known to be able to solve the problems of poor pharmacokinetic properties and low specificity. This led to the design of small molecules, non-peptide inhibitors, which were very potent and specific of human renin.
However, caused by their chemical structure even third-generation renin inhibitors are difficult to resorb by the human body and their oral bioavailability is often below 2%.
Binding and structure activity relationship of renin inhibitors The renin molecule is a monospecific enzyme that belongs to the aspartic protease family. Its structure is complex and consists of two homologous lobes that fold mainly in a β-sheet conformation. Between the two lobes, deep within the enzyme, resides the active site, and its catalytic activity is due to two aspartic acid residues (Asp32 and Asp 215, one from each lobe in the renin molecule). A flexible flap made from amino acids formed in a β-hairpin closes the active site by covering the cleft.