Renin inhibitor

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Renin inhibitor
C09XA
Biological targetRenin
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In Wikidata

Renin inhibitors are

angiotensin II that facilitates blood pressure.[5][6]

Renin inhibitor is often preceded by direct, called direct renin inhibitor in order to distinguish its mechanism from other

aldosterone receptor antagonists.[6]

These drugs

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.[7][8] 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.[7] As of June 2020
, it is the only renin inhibitor on the market.

History

In 1896, the Finnish physiologist

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.[7]

angiotensinogen.[13] However, these inhibitors had also limited drug-like properties.[7][12] Hopes of breakthrough appeared in 1982 when development of the second generation renin inhibitors began.[7] This generation consisted of peptide-like compounds, such as remikiren, enalkiren and zanikiren.[11] 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.[7]

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.

US Food and Drug Administration and the European Medicines Agency as a treatment for hypertension.[7] A systematic review by the Cochrane Hypertension group found the maximum recommended dose of aliskiren produced an appreciable decline in blood pressure over placebo.[16]

Timeline: Discovery and development of renin inhibitors

The renin–angiotensin–aldosterone system

Renin–angiotensin–aldosterone system and potential steps of blockage

The

total peripheral resistance and cardiac output
.

The highly

Ang II receptors, AT1 and AT2.[20] 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.[23] 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.[21] 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.[21] However, the role of plasma renin levels in the etiology and management of hypertension is disputed.[24]

Mechanism of action

Renin inhibitors bind to the

angiotensin II receptor antagonists.[27]
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
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.[28]

Drug discovery and development

Pepstatin – the first renin inhibitor

hydrophobic properties of statine, pepstatin has very low solubility in physiological media.[34]
Since it had low potency and poor solubility, it did not enter in vivo studies.

First generation: peptide analogues

H-142[clarification needed]

This generation consists of two groups of compounds, either peptide analogues of the prosegment of renin

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.[28]

Second generation: peptide mimetics

Remikiren, a second-generation renin inhibitor

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.[12] 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.[7][22][28]

Third generation: non-peptides

Aliskiren, the third-generation renin inhibitor

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.[22][40]

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.[41] Its structure is complex and consists of two homologous lobes that fold mainly in a β-sheet conformation.[22] 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).[42] A flexible flap made from amino acids formed in a β-hairpin closes the active site by covering the cleft.[43] 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[44] that can accommodate a ligand with at least seven residues. The principal connection between a ligand and the enzyme is by hydrogen bonding. The residues are named after their places in the ligand, the residues closest to the cleavage site are named P1 and P1′ and they bind into the S1 and S1′ pockets, respectively. There are four S pockets, and three S′ pockets (table 1). The pockets alternate on either side of the backbone in the ligand. This alternation affects the orientation of the pockets, making the S3 and S1 pockets arrange together and the S2 pocket close to both S4 and S1′ pockets.[43] Evidence suggests the closely arranged S1 and S3 pockets merge to form a spacious superpocket.[45]
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.[11] From the S3 pocket stretches a binding site distinct for renin, the S3sp subpocket.[41] The S3sp subpocket can accommodate both hydrophobic and
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.[11]

Binding pockets with which aliskiren connects
Characteristics of each pocket and the importance each residue in the ligand has to binding
Pocket Characteristics[11] Subsite Importance to binding[11][46]
S4 Hydrophobic P4 Relatively important for binding
S3 Hydrophobic P3 Very important for binding
S3sp Equally hydrophobic/-philic P3 side chain Dramatically enhances binding affinity
S2 Large and hydrophobic P2 Important for binding
S1 Large and hydrophobic P1 NA
S1′ Primarily hydrophobic P1′ Critical for tight binding
S2′ Polar P2′ Critical for tight binding
S3′ NA P3′ Structure and presence is not as important

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.[47] By having a large and

aromatic residue in P3 increases inhibitory activity.[48] Occupation of the S3sp subpocket can increase potency by 50-fold and results in tight binding.[11]

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.[46] The side chain of aliskiren binds the S3sp subpocket ideally, and leads to its quality as an inhibitor of human renin.[11] The hydroxyl group in aliskiren forms a hydrogen bond with both oxygen atoms of the

propyl groups in positions P1 and P1′.[45] 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.[49]

Current status

Aliskiren is effective in lowering blood pressure,[7][28] 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] < 60 mL/min). However, they also recommend that patients should not stop taking aliskiren without talking to a healthcare professional.[50]

Aliskiren in combination with hydrochlorothiazide was approved by the FDA in 2008 under the tradename Tekturna HCT.[51][52]

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

preclinical phases, the compound SPP1234 and compounds from the SPP800 series.[51]

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.[51][unreliable source]

See also

References

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External links

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