The control of hypertension and associated cardiovascular risk factors is possible by selective inhibition of the aspartyl protease renin due to its unique position in the renin-angiotensin system. Starting from a previously disclosed series of potent and nonchiral indole-3-carboxamides, we further explored this motif by structure-based drug design guided by X-ray crystallography in combination with efficient parallel synthesis. This resulted in the discovery of 4- or 6-azaindole derivatives with remarkable potency for renin inhibition. The best compound from these series showed an IC(50) value of 1.3 nM.
Copyright © 2011. Published by Elsevier Ltd.