Discovery and optimization of a new class of potent and non-chiral indole-3-carboxamide-based renin inhibitors |
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Authors: | Bodo Scheiper Hans Matter Henning Steinhagen Ulrich Stilz Zsolt Böcskei Valérie Fleury Gary McCort |
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Institution: | 1. Sanofi-Aventis Deutschland GmbH, Chemical and Analytical Sciences, Building G878, D-65926 Frankfurt, Germany;2. Sanofi-Aventis, Chemical and Analytical Sciences, 16, Rue d’Ankara, F-67080 Strasbourg, France;3. Sanofi-Aventis, Cardiovascular Department, 1, Avenue Pierre Brossolette, F-91385 Chilly-Mazarin, France |
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Abstract: | Selective inhibition of the aspartyl protease renin has gained attraction as an interesting approach to control hypertension and associated cardiovascular risk factors given its unique position in the renin–angiotensin system. Using a combination of high-throughput screening, parallel synthesis, X-ray crystallography and structure-based design, we identified and optimized a novel series of potent and non-chiral indole-3-carboxamides with remarkable potency for renin. The most potent compound 5k displays an IC50 value of 2 nM. |
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