Details

Autor(en) / Beteiligte

• Close, Joshua
• Heidebrecht, Richard
• Hendrix, John
• Li, Chaomin
• Munoz, Ben
• Surdi, Laura
• Kattar, Solomon
• Tempest, Paul
• Moses, Paul
• Geng, Xiaoliu
• Hughes, Bethany
• Smotrov, Nadya
• Moxham, Chris
• Chapnick, Jennifer
• Kariv, Ilona
• Nikov, George
• Burke, Julie Elizabeth
• Deshmukh, Sujal
• Jeliazkova-Mecheva, Valentina
• Leach, John Kevin
• Diaz, Damaris
• Xu, Lin
• Yang, Ziping
• Kwei, Gloria
• Moy, Lily
• Shah, Sanjiv
• Tanga, Flobert
• Kenefic, Candia
• Savage, Dan
• Shearman, Mark
• Ball, Richard G.
• McNevin, Michael J.
• Markarewicz, Amanda
• Miller, Thomas

Titel

Lead optimization of 4,4-biaryl piperidine amides as γ-secretase inhibitors

Ist Teil von

• Bioorganic & medicinal chemistry letters, 2012-05, Vol.22 (9), p.3203-3207

Ort / Verlag

Amsterdam: Elsevier Ltd

Erscheinungsjahr

2012

Quelle

MEDLINE

Beschreibungen/Notizen

• 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.