VTP-27999

VTP-27999 is a highly potent and selective renin inhibitor (IC50 = 0.47 nM). It exhibits >1000 selectivity for renin over >150 receptors, ion channels and enzymes.

Renin is an asparyl protease that cleaves angiotensinogen into angiotension I in the plasma. It functions as a regulator of blood pressure and sodium homeostasis.

In vitro, VTP-27999 increases renin immunoreactivity by ≥30%, it bind to acid-activated, intact prorenin and promotes immunoreactivity in a renin assay. In vascular smooth muscle cells, VTP-27999 also blocks renin's ability to activate extracellular signal-regulated kinase 1/2 phosphorylation. [1]

In double transgenic rats engineered to express human renin and angiotensinogen with severe hypertension, 24h treatment of 10 mg/kg VTP-27999 induces a greater reduction in mean arterial blood pressure and a longer duration of action. [2]

References:
1.  Krop M, Lu X, Verdonk K, Schalekamp MA et al. New renin inhibitor VTP-27999 alters renin immunoreactivity and does not unfold prorenin. Hypertension. 2013 May;61(5):1075-82.
2.  Jia L, Simpson RD, Yuan J et al. Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility. ACS Med Chem Lett. 2011 Aug 9;2(10):747-51.

Renin inhibitor VTP-27999 differs from aliskiren: focus on their intracellular accumulation and the (pro)renin receptor.[Pubmed:24637873]

J Hypertens. 2014 Jun;32(6):1255-63.

BACKGROUND: VTP-27999 is a renin inhibitor with an IC50 that is comparable to that of aliskiren, but with a higher bioavailability. Unexpectedly, VTP-27999, unlike aliskiren, did not unfold renin's precursor, prorenin, and increased the affinity of the antibodies applied in renin immunoassays. METHODS: Here we verified to what degree these differences affect intracellular renin inhibitor accumulation in renin-synthesizing human mast cells (HMC-1), and (pro)renin's signaling via the (pro)renin receptor ((P)RR) in rat vascular smooth muscle cells. We also addressed the consequences of (P)RR knockdown by small-interfering (si) RNA on (pro)renin release. Finally, making use of FRET(Bodipy-FL)-labeled aliskiren, we studied, by subcellular fractionation, the cellular distribution pattern of this renin inhibitor. RESULTS: VTP-27999 accumulated at higher levels in HMC-1 cells than aliskiren, allowing this inhibitor to block intracellular renin at approximately five-fold lower medium levels. Labeled aliskiren accumulated in mitochondria and lysosomes, and its distribution pattern was different from that of renin. Moreover, the intracellular accumulation of both inhibitors in nonrenin-synthesizing HEK293 cells was not different from that in HMC-1 cells, suggesting that it is renin synthesis-independent. VTP-27999, but not aliskiren, blocked renin's capacity to stimulate extracellular signal-regulated kinase 1/2 phosphorylation in vascular smooth muscle cells, whereas neither inhibitor interfered with prorenin-induced signaling. (P)RR knockdown greatly increased renin (and to a lesser degree, prorenin) release, without affecting the capacity of forskolin or cAMP to stimulate renin release. CONCLUSION: VTP-27999 differs from aliskiren regarding its level of intracellular accumulation and its capacity to interfere with renin signaling via the (P)RR, and the (P)RR determines prorenin-renin conversion and constitutive (but not regulated) (pro)renin release.

New renin inhibitor VTP-27999 alters renin immunoreactivity and does not unfold prorenin.[Pubmed:23460288]

Hypertension. 2013 May;61(5):1075-82.

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 IC50 and t1/2, and a much higher bioavailability. This study addressed (pro)renin changes during treatment of volunteers with VTP-27999 or aliskiren. Both drugs increased renin immunoreactivity. Treatment of plasma samples from aliskiren-treated subjects with excess aliskiren yielded higher renin immunoreactivity levels, confirming the presence of prorenin. Unexpectedly, this approach did not work in VTP-27999-treated subjects, although an assay detecting the prosegment revealed that their blood still contained prorenin. Subsequent in vitro analysis showed that VTP-27999 increased renin immunoreactivity for a given amount of renin by >/= 30% but did not unfold prorenin. Yet, it did bind to acid-activated, intact prorenin and then again increased immunoreactivity in a renin assay. However, no such increase in immunoreactivity was seen when measuring acid-activated prorenin bound to VTP-27999 with a prosegment-directed assay. The VTP-27999-induced rises in renin immunoreactivity could be competitively prevented by aliskiren, and antibody displacement studies revealed a higher affinity of the active site-directed antibodies in the presence of VTP-27999. In conclusion, VTP-27999 increases renin immunoreactivity in renin immunoassays because it affects the affinity of the active site-directed antibody. Combined with its lack of effect on prorenin, these data show that VTP-27999 differs from aliskiren. The clinical relevance of these results needs to be established.

Maximum renal responses to renin inhibition in healthy study participants: VTP-27999 versus aliskiren.[Pubmed:26882043]

J Hypertens. 2016 May;34(5):935-41.

BACKGROUND: Renin inhibition with aliskiren induced the largest increases in renal plasma flow (RPF) in salt-depleted healthy volunteers of all renin-angiotensin system (RAS) blockers. However, given its side-effects at doses higher than 300 mg, no maximum effect of renin inhibition could be established. We hypothesized that VTP-27999, a novel renin inhibitor without major side-effects at high doses, would allow us to establish this. METHODS AND RESULTS: The effects of escalating VTP-27999 doses (75-600 mg) on RPF, glomerular filtration rate (GFR), and plasma RAS components were compared with those of 300 mg aliskiren in 22 normal volunteers on a low-sodium diet. VTP-27999 dose-dependently increased RPF and GFR; its effects on both parameters at 600 mg (increases of 18 +/- 4 and 20 +/- 4%, respectively) were equivalent to those at 300 mg, indicating that a maximum had been reached. The effects of 300 mg aliskiren (increases of 13 +/- 5 and 8 +/- 6%, respectively; P < 0.01 vs. 300 and 600 mg VTP-27999) resembled those of 150 mg VTP-27999. VTP-27999 dose-dependently increased renin, and lowered plasma renin activity and angiotensin II to detection limit levels. The effects of aliskiren on RAS components were best comparable to those of 150 mg VTP-27999. CONCLUSION: 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.

Multiple ascending dose study with the new renin inhibitor VTP-27999: nephrocentric consequences of too much renin inhibition.[Pubmed:24470465]

Hypertension. 2014 May;63(5):942-50.

This study compared the pharmacodynamic/pharmacokinetic profile of the new renin inhibitor VTP-27999 in salt-depleted healthy volunteers, administered once daily (75, 150, 300, and 600 mg) for 10 days, versus placebo and 300 mg aliskiren. VTP-27999 was well tolerated with no significant safety issues. It was rapidly absorbed, attaining maximum plasma concentrations at 1 to 4 hours after dosing, with a terminal half-life of 24 to 30 hours. Plasma renin activity remained suppressed during the 24-hour dosing interval at all doses. VTP-27999 administration resulted in a dose-dependent induction of renin, increasing the concentration of plasma renin maximally 350-fold. This induction was greater than with aliskiren, indicating greater intrarenal renin inhibition. VTP-27999 decreased plasma angiotensin II and aldosterone. At 24 hours and later time points after dosing on day 10 in the 600-mg group, angiotensin II and aldosterone levels were increased, and plasma renin activity was also increased at 48 and 72 hours, compared with baseline. VTP-27999 decreased urinary aldosterone excretion versus placebo on day 1. On day 10, urinary aldosterone excretion was higher in the 300- and 600-mg VTP-27999 dose groups compared with baseline. VTP-27999 decreased blood pressure to the same degree as aliskiren. In conclusion, excessive intrarenal renin inhibition, obtained at VTP-27999 doses of 300 mg and higher, is accompanied by plasma renin rises, that after stopping drug intake, exceed the capacity of extrarenal VTP-27999 to block fully the enzymatic reaction. This results in significant rises of angiotensin II and aldosterone. Therefore, renin inhibition has an upper limit.