Document Detail

Lead optimization of 4,4-biaryl piperidine amides as γ-secretase inhibitors.
MedLine Citation:
PMID:  22483609     Owner:  NLM     Status:  Publisher    
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.
Joshua Close; Richard Heidebrecht; John Hendrix; Chaomin Li; Ben Munoz; Laura Surdi; Solomon Kattar; Paul Tempest; Paul Moses; Xiaoliu Geng; Bethany Hughes; Nadya Smotrov; Chris Moxham; Jennifer Chapnick; Ilona Kariv; George Nikov; Julie Elizabeth Burke; Sujal Deshmukh; Valentina Jeliazkova-Mecheva; John Kevin Leach; Damaris Diaz; Lin Xu; Ziping Yang; Gloria Kwei; Lily Moy; Sanjiv Shah; Flobert Tanga; Candia Kenefic; Dan Savage; Mark Shearman; Richard G Ball; Michael J McNevin; Amanda Markarewicz; Thomas Miller
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Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2012-3-17
Journal Detail:
Title:  Bioorganic & medicinal chemistry letters     Volume:  -     ISSN:  1464-3405     ISO Abbreviation:  -     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-4-9     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  9107377     Medline TA:  Bioorg Med Chem Lett     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
Copyright © 2012 Elsevier Ltd. All rights reserved.
Merck Research Laboratories, 33 Avenue Louis Pasteur, Boston, MA 02115, USA.
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