Renin Inhibitors: A Journey Through Polarity, Size and Potency



July 21, 2011

More than ten years ago, seminal publications disclosed a new class of 3,4-disubstituted piperidines as potent renin inhibitors (E. Vieira, et al., Bioorg. Med. Chem. Lett., 1999, 9, 1397). In spite of their potency, a pour pharmacokinetic profile made these compounds unsuitable for further drug development. We hypothesized that this pour profile might be related to the large molecular weight and high lipophilicity of these compounds. In this presentation we will explore different possibilities to increase the polarity and decrease the size of such compounds, while maintaining their potency. We will explore different exit vectors projecting toward the bulk solvent. We will explore possibilities to increase the polarity on substituents filling the P1- and P3 pockets, as well as on a substituent filling a pocket placed under the flap of the enzyme. Possibilities to decrease the size of such inhibitors will be discussed as well. A fine balance between CYP liabilities, bioavailability, and in vivo potency in double transgenic rats over-expressing the human genes for renin and angiotensinogen, will be studied.

Analytical TechniquesChemistryDrug DiscoveryMolecular Biology

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