The objective of the study is to determine the magnitude of the effect of direct renin inhibition by VTP-27999 on renal plasma flow and kidney function.

开始日期2010-09-01

申办/合作机构

Vitae Pharmaceuticals LLC

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100 项与 VTP-27999 相关的临床结果

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100 项与 VTP-27999 相关的转化医学

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100 项与 VTP-27999 相关的专利（医药）

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项与 VTP-27999 相关的文献（医药）

2017-02-01·Journal of Hypertension2区 · 医学

Do prorenin-synthesizing cells release active, ‘open’ prorenin?

2区 · 医学

Article

作者: Danser, A. H. Jan ; Garrelds, Ingrid M. ; Saleh, Langeza ; Martini, Alexandre G. ; Krop, Manne

BACKGROUNDThe function of prorenin, the inactive precursor of renin, remains unclear after many decades of research. The discovery of a (pro)renin receptor suggested that prorenin, by binding to this receptor, would become active, that is, obtain an 'open' conformation. However, the receptor only interacted with prorenin at levels that were many orders of magnitude above its normal levels, making such interaction in-vivo unlikely. Prorenin occurs in two conformations, an open, active form, and a closed, inactive form. Under physiological conditions (pH 7.4, 37 °C), virtually all prorenin occurs in the closed conformation. This study investigated to what degree prorenin-synthesizing cells release prorenin in an open conformation.METHODS AND RESULTSRenin plus prorenin-synthesizing human mast cells, and prorenin-synthesizing HEK293 cells (transfected with the mammalian expression vector pRhR1100, containing human prorenin) and human decidua cells were incubated with the renin inhibitor VTP-27999. This inhibitor will trap open prorenin, as after VTP-27999 binding, prorenin can no longer return to its closed conformation, thus allowing its detection in a renin immunoradiometric assay. No evidence for the release of open prorenin was found. Moreover, incubating decidua cells with angiotensinogen yielded low angiotensin levels, corresponding with the activity of ≈1% of prorenin in the medium, that is, the amount of open prorenin expected based upon the equilibrium between open and closed prorenin under physiological conditions.CONCLUSIONOur study does not reveal evidence for the release of open, active prorenin by prorenin-synthesizing cells, at least under cell culture conditions. This argues against prorenin activity at the site of its release.

2016-05-01·Journal of Hypertension2区 · 医学

Maximum renal responses to renin inhibition in healthy study participants

2区 · 医学

Article

作者: Moukarbel, George V. ; Barkoudah, Ebrahim ; Danser, A. H. Jan ; Fisher, Naomi D. L. ; Gregg, Richard A. ; van Thiel, Bibi S. ; Hollenberg, Norman K.

BACKGROUNDRenin 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 RESULTSThe 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.CONCLUSIONMaximum 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.

2014-06-01·Journal of Hypertension2区 · 医学

Renin inhibitor VTP-27999 differs from aliskiren

2区 · 医学

Article

作者: Danser, A. H. Jan ; Garrelds, Ingrid M. ; Lu, Xifeng ; Musterd-Bhaggoe, Usha M. ; Batenburg, Wendy W. ; Krop, Manne

BACKGROUNDVTP-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.METHODSHere 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.RESULTSVTP-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.CONCLUSIONVTP-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.

100 项与 VTP-27999 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
-	-	-	DB12416

研发状态

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适应症	最高研发状态	国家/地区	公司	日期
慢性肾病	临床1期	-	Vitae Pharmaceuticals LLC	-
高血压	临床1期	美国	Vitae Pharmaceuticals LLC	-
肾脏疾病	临床1期	美国	Vitae Pharmaceuticals LLC	-