title: New renin inhibitor VTP-27999 alters renin immunoreactivity and does not unfold prorenin.
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 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.
authors: Department of Internal Medicine, Division of Pharmacology and Vascular Medicine, Erasmus MC, Rotterdam, The Netherlands.
authors: Manne
authors: M
authors: Krop
authors: Xifeng
authors: X
authors: Lu
authors: Koen
authors: K
authors: Verdonk
authors: Maarten A D H
authors: MA
authors: Schalekamp
authors: Jeanette M G
authors: JM
authors: van Gool
authors: Brian M
authors: BM
authors: McKeever
authors: Richard
authors: R
authors: Gregg
authors: A H Jan
authors: AH
authors: Danser
mesh_terms: D000328:Adult; D000577:Amides / Q000494:pharmacology*; D002219:Carbamates / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005260:Female; D005650:Fumarates / Q000494:pharmacology*; D006207:Half-Life; D006801:Humans; D007118:Immunoassay; D008297:Male; D010880:Piperidines / Q000494:pharmacology; D011485:Protein Binding / Q000187:drug effects; D058767:Protein Unfolding / Q000187:drug effects*; D012083:Renin / Q000097:blood / Q000737:chemistry* / Q000187:drug effects / Q000276:immunology*; D000092502:Renin Inhibitors
chemical_list: D000577:Amides; D002219:Carbamates; D005650:Fumarates; D010880:Piperidines; D012083:Renin; D000092502:Renin Inhibitors; C582069:methyl (2-((3-chlorophenyl)(1-((2-(methylamino)-3-(tetrahydro-2H-pyran-3-yl)propyl)carbamoyl)piperidin-3-yl)methoxy)ethyl)carbamate; C446481:aliskiren