Antihypertensives: Renin Inhibitors

Abstract

Renin has been recognized as an attractive target for antihypertensive drugs since the 1950s. Intensive efforts in the 1980s focused on peptidomimetic hydroxy transition‐state isosteres led to many potent renin inhibitors. However, none of these compounds was developed as a drug. The advent of routine X‐ray crystallography of protein–ligand complexes provided additional insights that culminated in the discovery of aliskiren, a fully nonpeptidic renin inhibitor. Aliskiren, the first direct renin inhibitor to reach the market, was approved as an antihypertensive in 2007. Preliminary clinical trials suggest that aliskiren, and potentially other direct renin inhibitors, may have utility in end organ protection and congestive heart failure, in addition to hypertension.

Discovery of DS-8108b, a Novel Orally Bioavailable Renin Inhibitor

“…However, because of their poor oral bioavailability, none of these inhibitors was successfully developed as a drug. 8 Beginning in the middle of the 1990s, several novel nonpeptidic renin inhibitors were reported and have entered human clinical trials, such as aliskiren hemifumarate (1), 9 ACT-077825 (MK-8141) (2), 10 and VTP-27999 (3) 11 (Figure 1). Despite significant research investments from the pharmaceutical industry directed toward the discovery of renin inhibitors suitable for clinical development, 12,13 only aliskiren has been launched to the market for the treatment of hypertension to date.…”

“…During the 1980s, all of the first generation renin inhibitors were peptides or peptidomimetics that incorporated peptide hydrolysis transition state isosteres. However, because of their poor oral bioavailability, none of these inhibitors was successfully developed as a drug . Beginning in the middle of the 1990s, several novel nonpeptidic renin inhibitors were reported and have entered human clinical trials, such as aliskiren hemifumarate ( 1 ), ACT-077825 (MK-8141) ( 2 ), and VTP-27999 ( 3 ) (Figure ).…”

Discovery of VTP-27999, an Alkyl Amine Renin Inhibitor with Potential for Clinical Utility

“…Renin has proved to be a historically challenging target for medicinal chemists. During the 1980s, intensive efforts that focused on peptidomimetics led to the discovery of many potent compounds; , however, because of poor oral bioavailability, none of them was successfully developed as a drug . Beginning in the mid-1990s, several classes of nonpeptidic renin inhibitors were reported. − One line of investigation culminated in the discovery of aliskiren ( 1 , Figure ), the first approved DRI, which was brought to market in 2007 …”