Lead optimization of 4,4-biaryl piperidine amides as γ-secretase inhibitors
| Autor: | George N. Nikov, Flobert Tanga, Chris Moxham, Ziping Yang, Chaomin Li, Richard G. Ball, Joshua Close, Richard W. Heidebrecht, Gloria Y. Kwei, Lin Xu, Laura Surdi, Xiaoliu Geng, Candia Kenefic, Sanjiv J. Shah, Dan F. Savage, Valentina V. Jeliazkova-Mecheva, Jennifer Chapnick, Julie Elizabeth Burke, Solomon Kattar, Bethany Hughes, Lily Y. Moy, Sujal V. Deshmukh, Paul Moses, Damaris Diaz, John Kevin Leach, Paul Tempest, John Hendrix, Amanda Markarewicz, Nadya Smotrov, Ilona Kariv, Michael J. McNevin, Ben Munoz, Mark S. Shearman, Thomas A. Miller |
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| Rok vydání: | 2012 |
| Předmět: |
Clinical Biochemistry
Pharmaceutical Science Pharmacology Biochemistry chemistry.chemical_compound Mice Pharmacokinetics Piperidines In vivo Alzheimer Disease Drug Discovery Extracellular Animals γ secretase Enzyme Inhibitors Molecular Biology chemistry.chemical_classification Amyloid beta-Peptides Organic Chemistry Brain Amides In vitro Peptide Fragments Enzyme chemistry Molecular Medicine Piperidine Amyloid Precursor Protein Secretases |
| Zdroj: | Bioorganicmedicinal chemistry letters. 22(9) |
| ISSN: | 1464-3405 |
| Popis: | Alzheimer’s disease is a major unmet medical need with pathology characterized by extracellular proteinaceous plaques comprised primarily of β-amyloid. γ-Secretase is a critical enzyme in the cellular pathway responsible for the formation of a range of β-amyloid peptides; one of which, Aβ42, is believed to be responsible for the neuropathological features of the disease. Herein, we report 4,4 disubstituted piperidine γ-secretase inhibitors that were optimized for in vitro cellular potency and pharmacokinetic properties in vivo. Key agents were further characterized for their ability to lower cerebral Aβ42 production in an APP-YAC mouse model. This structural series generally suffered from sub-optimal pharmacokinetics but hypothesis driven lead optimization enabled the discovery of γ-secretase inhibitors capable of lowering cerebral Aβ42 production in mice. |
| Databáze: | OpenAIRE |
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