1. The discovery and synthesis of potent zwitterionic inhibitors of renin
- Author
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Stephen M. Soisson, Tom Y.-H. Wu, Michel Gallant, Austin Chen, Dwight Macdonald, Daniel Dube, Robert Houle, Jean-Pierre Falgueyret, Renee Aspiotis, Dan McKay, Jean-François Lévesque, Patrick Roy, Helene Juteau, Sébastien Gagné, M. David Percival, Erich L. Grimm, Sebastien Laliberte, Patrick Lacombe, and Elizabeth Cauchon
- Subjects
Stereochemistry ,Carboxylic acid ,Clinical Biochemistry ,hERG ,Drug Evaluation, Preclinical ,Administration, Oral ,Pharmaceutical Science ,Biochemistry ,Chemical synthesis ,Rats, Sprague-Dawley ,Structure-Activity Relationship ,chemistry.chemical_compound ,Dogs ,Piperidines ,Catalytic Domain ,Renin ,Drug Discovery ,Animals ,Humans ,Structure–activity relationship ,Computer Simulation ,Protease Inhibitors ,Molecular Biology ,chemistry.chemical_classification ,biology ,Organic Chemistry ,Prodrug ,Rats ,Enzyme ,chemistry ,Enzyme inhibitor ,Zwitterion ,biology.protein ,Molecular Medicine - Abstract
The incorporation of a carboxylic acid within in a series of 3-amido-4-aryl substituted piperidines (represented by general structure 32) led to the discovery of potent, zwitterionic, renin inhibitors with improved off-target profiles (CYP3A4 time-dependent inhibition and hERG affinity) relative to analogous non-zwitterionic inhibitors of the past (i.e., 3). Strategies to address the oral absorption of these zwitterions are also discussed within.
- Published
- 2011