SPH3127

SPH3127 appears to be a very potent DRI with much improved PK properties compared to the authors earlier compounds. Further, this probe shows similar IC50 values in both the re-renin (recombinant enzyme) and hPRA (plasma) assays indicating that unlike previous small molecule DRIs, plasma protein binding does not appear to be an issue. Regarding the control compound (Cmpd 10), there appears to be much less published information that could inform animal model studies with this as a negative control, however, the in vitro potency against both rh-renin (159 nM) and hPRA (661 nM) suggest that it is suitable for in vitro studies. The double transgenic Tsukuba Hypertensive Mice (HTM) model and the cynomolgus monkey pretreated with a low-sodium diet and furosemide models used by the authors seem to be well suited to studying the antihypertensive effects of DRIs such as the probe SPH3127. As with previous small molecule DRIs (Direct Renin Inhibitors), these compounds will likely show very poor activity against the rat isozyme, and thus must be tested in an animal model such as the double transgenic Tsukuba Hypertensive Mice (HTM) model carrying both the human angiotensinogen and the human renin genes.