Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility

Jia, Lanqi; Simpson, R. David; Yuan, Jing; Xu, Zhixiang; Zhao, Wei; Cacatian, Salvacion; Tice, Colin M.; Guo, Joan; Ishchenko, Alexey; Singh, Suresh B.; Wu, Zhenyong; McKeever, Brian; Bukhtiyarov, Yuri; Johnson, Judith A.; Doe, Christopher P.; Harrison, Richard K.; McGeehan, Gerard M.; Dillard, Lawrence W.; Baldwin, John J.; Claremon, David A.

doi:10.1021/ml200137x

Cited by 34 publications

(27 citation statements)

References 24 publications

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“…An explanation for the different consequences of inhibitor binding is that aliskiren would be more effective than VTP-27999 at displacing the Ser3 to Asp11 segment from the binding site, which in turn pushes out the prosegment (Figures S5-S8). 9,14,17,18 The stability of the prosegment conformation is only hinted at by the solution of the prorenin crystal structure ( Figure S9), which provides a time-and space-averaged snapshot of the zymogen. Understanding the dynamics of this portion of the prorenin structure would shed light on how these particular inhibitors interact with the protein and vice versa.…”

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confidence: 99%

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New Renin Inhibitor VTP-27999 Alters Renin Immunoreactivity and Does Not Unfold Prorenin

Krop

Lu²,

Verdonk³

et al. 2013

Hypertension

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R enin belongs to the A1 family of aspartic proteases. Its 3-dimensional (3D) structure consists of 2 β-sheet domains (N and C domain) related by an ≈2-fold axis. The active site is a deep cleft between the N and C domains that extends over 8 residues of renin's substrate, angiotensinogen. Each domain supplies 1 catalytic aspartic acid residue in the center of the binding cleft. A long β-hairpin loop structure called the flap in the N-terminal domain covers the central part of the angiotensinogen-binding site, and the conformation with the tip of the flap open allows the entrance of the substrate and removal of hydrolytic products during the catalytic turnover, while the tip closes on substrate binding. 1 In the case of renin's inactive precursor, prorenin, the flap is open to accommodate the 43-amino acid prosegment.1,2 Morales et al 2 recently proposed that in prorenin, the catalytic binding site is covered by the N-terminal part of mature renin that, in turn, is covered by the prosegment. After removal of the prosegment, this N-terminal part becomes part of a 6-stranded β-sheet on the back of the mature renin molecule, previously occupied by the prosegment. This requires a conformational change that fully exposes the active cleft. 2Prosegment unfolding occurs in a pH-and temperaturedependent manner and, if not followed by cleavage, results in 2 prorenin conformations as follows: a closed, inactive form, and an open form that displays full enzymatic activity (Figure 1). 3,4 In addition, an intermediate form exists where the prosegment has moved away from the cleft, but where the renin part still has to undergo the above-mentioned conformational changes. Under physiological conditions, <2% of prorenin is in the open conformation. The recently introduced renin inhibitor, aliskiren ( Figure S1A in the online-only Data Supplement), binds to prorenin in the open conformation, as well as to the intermediate form of prorenin. 3,4 Binding to the intermediate form induces prorenin unfolding. Because of the tight binding of the renin inhibitor, the refolding step (ie, the return to the closed conformation) is no longer possible, and thus the equilibrium between the closed and open conformation will shift in favor of the open conformation. Eventually, depending on the concentration of aliskiren, a significant proportion of prorenin may be open (nonproteolytic activation), allowing its recognition by the active site-directed antibodies used in renin immunoradiometric assays (IRMAs), despite the fact that the Abstract-Renin inhibitors like aliskiren not only block renin but also bind prorenin, thereby inducing a conformational change (like the change induced by acid) allowing its recognition in a renin-specific assay. Consequently, aliskiren can be used to measure prorenin. VTP-27999 is a new renin inhibitor with an aliskiren-like IC 50 and t 1/2 , and a much higher bioavailability. This study addressed (pro)renin changes during treatment of volunteers with VTP-27999 or aliskiren. Both drugs increased renin immunoreactivi...

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“…9 This study tested the changes in renin and prorenin during a 10-day treatment of salt-depleted volunteers with 150 mg VTP-27999, focusing on the possibility that the VTP-27999-induced rise in renin is attributable, at least in part, to prorenin unfolding. Remarkably, this turned out not to be the case.…”

mentioning

confidence: 99%

New Renin Inhibitor VTP-27999 Alters Renin Immunoreactivity and Does Not Unfold Prorenin

Krop

Lu²,

Verdonk³

et al. 2013

Hypertension

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“…These data are drawn assuming that the highest dosage of aliskiren used in clinical practice (300 mg) substantially reflects the top of its dose response and the most complete renin inhibition [63]. From preclinical data about analogues of aliskiren, such as the compound developed by Vitae (Pharmaceutical Inc., Washington, Pennsylvania, USA), it can be hypothesized that larger doses would have greater potency, although at this stage we can only speculate about this [64].…”

Section: Angiotensin-converting Enzyme Inhibition or Angiotensin Typementioning

confidence: 99%

Inhibition of the renin–angiotensin–aldosterone system

Volpe

Danser

Ménard

et al. 2012

Journal of Hypertension

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Antagonism of renin-angiotensin-aldosterone system is exerted through angiotensin-converting enzyme inhibitors, angiotensin receptor antagonists, renin inhibitors and mineralocorticoid receptor antagonists. These drugs have been successfully tested in numerous trials and in different clinical settings. The original indications of renin-angiotensin-aldosterone system blockers have progressively expanded from the advanced stages to the earlier stages of cardiorenal continuum. To optimize the degree of blockade of renin-angiotensin-aldosterone system, dose uptitrations of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists or the use of a dual blockade, initially identified with the combination of angiotensin-converting enzyme inhibitors and angiotensin receptor antagonists, have been proposed. The data from the Ongoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial (ONTARGET) study do not support this specific dual blockade approach. However, the dual blockade of angiotensin-converting enzyme inhibitors/angiotensin receptor antagonists with direct renin inhibitors is currently under investigation while that based on an aldosterone blocker with any of the previous three drugs requires more evidence beyond heart failure. In this review, we revisited potential advantages of dual blockade of renin-angiotensin-aldosterone system in arterial hypertension and diabetes.

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“…The drug was safe and well tolerated. As VTP-27999 is a potent renin inhibitor with an oral bioavailability that is about 10-fold higher than that of aliskiren [17,18], we hypothesized that, with the help of this new and well tolerated renin inhibitor, we would be able to establish the maximum effect of renin inhibition in the kidney. Therefore, in the present study, we compared the acute renal effects of escalating VTP-27999 doses (75-600 mg) with those of 300 mg aliskiren in healthy, salt-depleted volunteers.…”

Section: Introductionmentioning

confidence: 99%

Maximum renal responses to renin inhibition in healthy study participants

Barkoudah

Thiel

Fisher

et al. 2016

Journal of Hypertension

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Maximum renal renin blockade in healthy, salt-depleted volunteers, requires aliskiren doses higher than 300 mg, but can be established with 300 mg VTP-27999. To what degree such maximal effects (exceeding those of angiotensin-converting enzyme inhibitors and AT1-receptor blockers) are required in patients with renal disease, given the potential detrimental effects of excessive RAS blockade, remains to be determined.

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Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility

Cited by 34 publications

References 24 publications

New Renin Inhibitor VTP-27999 Alters Renin Immunoreactivity and Does Not Unfold Prorenin

New Renin Inhibitor VTP-27999 Alters Renin Immunoreactivity and Does Not Unfold Prorenin

Inhibition of the renin–angiotensin–aldosterone system

Maximum renal responses to renin inhibition in healthy study participants

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