VTP-27999 2,2,2-trifluoroacetate - CAS 1013937-63-7
Catalog number: 1013937-63-7
Category: Inhibitor
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VTP-27999 2,2,2-trifluoroacetate is an alkyl amine Renin inhibitor, useful for Hypertension and End-Organ Diseases.
VTP-27999; VTP27999; VTP 27999. VTP-27999 HCl; VTP-27999 TFA
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1.Multiple ascending dose study with the new renin inhibitor VTP-27999: nephrocentric consequences of too much renin inhibition.
Balcarek J1, Sevá Pessôa B, Bryson C, Azizi M, Ménard J, Garrelds IM, McGeehan G, Reeves RA, Griffith SG, Danser AH, Gregg R. Hypertension. 2014 May;63(5):942-50. doi: 10.1161/HYPERTENSIONAHA.113.02893. Epub 2014 Jan 27.
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.
2.Renin inhibitor VTP-27999 differs from aliskiren: focus on their intracellular accumulation and the (pro)renin receptor.
Lu X1, Krop M, Batenburg WW, Musterd-Bhaggoe UM, Garrelds IM, Danser AH. J Hypertens. 2014 Jun;32(6):1255-63. doi: 10.1097/HJH.0000000000000167.
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.
3.Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility.
Jia L1, Simpson RD1, Yuan J1, Xu Z1, Zhao W1, Cacatian S1, Tice CM1, Guo J1, Ishchenko A1, Singh SB1, Wu Z1, McKeever BM1, Bukhtiyarov Y1, Johnson JA1, Doe CP2, Harrison RK1, McGeehan GM1, Dillard LW1, Baldwin JJ1, Claremon DA1. ACS Med Chem Lett. 2011 Aug 9;2(10):747-51. doi: 10.1021/ml200137x. eCollection 2011.
Structure guided optimization of a series of nonpeptidic alkyl amine renin inhibitors allowed the rational incorporation of additional polar functionality. Replacement of the cyclohexylmethyl group occupying the S1 pocket with a (R)-(tetrahydropyran-3-yl)methyl group and utilization of a different attachment point led to the identification of clinical candidate 9. This compound demonstrated excellent selectivity over related and unrelated off-targets, >15% oral bioavailability in three species, oral efficacy in a double transgenic rat model of hypertension, and good exposure in humans.
4.New renin inhibitor VTP-27999 alters renin immunoreactivity and does not unfold prorenin.
Krop M1, Lu X, Verdonk K, Schalekamp MA, van Gool JM, McKeever BM, Gregg R, Danser AH. Hypertension. 2013 May;61(5):1075-82. doi: 10.1161/HYPERTENSIONAHA.111.00967. Epub 2013 Mar 4.
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.
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CAS 1013937-63-7 VTP-27999 2,2,2-trifluoroacetate

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(CAS: 1013937-63-7)

VTP-27999 2,2,2-trifluoroacetate is an alkyl amine Renin inhibitor, useful for Hypertension and End-Organ Diseases.

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CAS 1013937-63-7 VTP-27999 2,2,2-trifluoroacetate

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