Renin inhibitor

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.{{Cite journal

Pepstatin, which was described in 1972, was the first synthetic renin inhibitor, but poor pharmacokinetic properties prevented it from entering in vivo investigations.{{Cite journal | doi-access = free

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.{{Cite journal | doi-access = free | doi-access = free

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.{{Cite journal | doi-access = free | doi-access = free

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,{{Cite journal 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.{{Cite journal

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.{{Cite journal | doi-access = free | doi-access = free | doi-access = free

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.{{Cite journal

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.{{Cite journal

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.{{Cite journal The renin molecule contains both hydrophobic and hydrophilic amino acids. The hydrophilic ones tend to be on the outside of the molecule, while the hydrophobic ones tend to be more on the inside and form the active site, a large hydrophobic cavity{{Cite journal Ligands that fill the superpocket have greater potency than those which do not, occupying increases potency 200-fold. These ligands can be structurally diverse and form van der Waals bonds to the surface of the superpocket. From the S3 pocket stretches a binding site distinct for renin, the S3sp subpocket. The S3sp subpocket can accommodate both hydrophobic and polar residues, the pocket can accommodate three water molecules, but has also lipophilic nature. The S3sp subpocket is not conformationally flexible, so the residues occupying the pocket must have certain characteristics. They can not be sterically demanding and must have reasonably high number of rotatable bonds and be able to connect with hydrogen bonds. The S2 pocket is large, bipartite and hydrophobic, but can accommodate both hydrophobic and polar ligands. This diversity of possible polarity offers the P2 residue opportunity of variation in its connection to the enzyme. The S3-S1 and the S3sp subpockets have been the main target of drug design, but recent discoveries have indicated other sites of interest. Interactions to the pockets on the S′ site have been proven to be critical for affinity, especially the S1′ and S2′, and in vitro tests have indicated the interaction with the flap region could be important to affinity.

Interaction with both aspartic acids in the active site results in a higher affinity. Higher affinity also results by occupying more active site pockets. However, some pockets contribute more to the affinity than others. A hydrophobic interaction with the S3sp subpocket, S1 and S3 contribute to higher potency and affinity.{{Cite journal By having a large and aromatic residue in P3 increases inhibitory activity.{{Cite journal | doi-access = free

Example of binding to the renin inhibitor: Aliskiren is a peptide-like renin inhibitor and, unlike most, it is rather hydrophilic. It blocks the catalytic function of the enzyme by occupying the S3 to S2′ pockets, except the S2 pocket. Aliskiren also binds to the S3sp subpocket and because that pocket is distinct for renin, aliskiren does not inhibit other aspartic proteases, such as cathepsin D and pepsin. The side chain of aliskiren binds the S3sp subpocket ideally, and leads to its quality as an inhibitor of human renin. The hydroxyl group in aliskiren forms a hydrogen bond with both oxygen atoms of the Asp32. The amine group forms a hydrogen bond with the carboxylic acid group of Gly217 and the oxygen atom of the Asp32. The methoxy group on the aromatic ring fills the S3 pocket and may possibly form a hydrogen bond with a secondary amine group of Tyr14. The amide group forms a hydrogen bond with a secondary amine group of Ser76. The S1 and S1′ pockets are occupied by the two propyl groups in positions P1 and P1′. The terminal amide in position P2′ anchors the amide tail in the active site by forming a hydrogen bond with Arg74 in the S2′ pocket.{{Cite journal

Current status

Aliskiren is effective in lowering blood pressure, but as of 20 April 2012 the US Food and Drug Administration (FDA) issued a warning of possible risks when using aliskiren or blood pressure medicines containing aliskiren with ACE inhibitors and angiotensin receptor blockers (ARBs) in patients with diabetes or kidney (renal) impairment. They advised that such drug combinations should not be used in patients with diabetes because of the risk of causing renal impairment, hypotension, and hyperkalemia and that aliskiren should not be used with ARBs or ACE inhibitors in patients with moderate to severe renal impairment (i.e., where glomerular filtration rate [GFR]

Aliskiren in combination with hydrochlorothiazide was approved by the FDA in 2008 under the tradename Tekturna HCT.Speedel Acquiring an additional 51.7% stake and announcing plans for mandatory public tender offer.TRANSACTION OVERVIEW. (2008). From Novartis: http://www.novartis.com/downloads/investors/presentations-events/other-events/2008/2008-07_speedel-backgrounder.pdf

In 2007, Actelion/Merck and Speedel companies announced they had the next generation of renin inhibitors in clinical research. The lead compound from Actelion/Merck has entered phase II trials. One compound from Speedel, SPP635, has completed phase IIa. The results showed it was safe and well tolerated over a four-week period, and it reduced blood pressure by 9.8 to 17.9 mmHg. In 2008, SPP635 was continuing phase II development for hypertension in diabetic patients. More renin inhibitors from Speedel are in clinical trials. Two of them, SPP1148 and SPP676, have entered phase I. Other are in preclinical phases, the compound SPP1234 and compounds from the SPP800 series.

The next generation of renin inhibitors have shown potential improvements over previous generations where bioavailability has increased up to 30% in humans, and they have better tissue distribution.

References

References

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