Structure-based design and optimization of potent renin inhibitors on 5- or 7-azaindole-scaffolds

The selective inhibition of the aspartyl protease renin is of high interest to control hypertension and associated cardiovascular risk factors. Following on preceding contributions, we report herein on the optimization of two series of azaindoles to arrive at potent and non-chiral renin inhibitors. The previously discovered azaindole scaffold was further explored by structure-based drug design in combination with parallel synthesis. This results in the identification of novel 5- or 7-azaindole derivatives with remarkable potency for renin inhibition. The best compounds on both series show IC50 values between 3 and 8 nM.