molecules of the month

Context. SPH3127 (Mitsubishi Tanabe and Shanghai Pharmaceuticals) is an oral direct renin inhibitor (DRI) being developed for hypertension. The renin-angiotensin-aldosterone system is responsible for regulating blood pressure. Existing drugs treat hypertension by targeting angiotensin-converting enzyme (ACE) and the angiotensin II receptor. However, these drugs can lead to a feedback effect whereby plasma serum levels become elevated. Renin, the pathway’s first and rate-limiting enzyme, has been an attractive therapeutic target for decades since the identification of peptide-like renin inhibitors and renin’s structural determination. First and second-generation renin inhibitors were peptide analogues and transition state peptidomimetics, while third-generation compounds, guided by structure-based design, yielded non-peptidomimetic synthetic compounds such as aliskiren, which was approved in 2007. Aliskiren suffered from low oral bioavailability, and…