Synthesis and evaluation of a novel 2-azabicyclo[2.2.2]octane class of long chain fatty acid elongase 6 (ELOVL6) inhibitors

A series of novel 2-azabicyclo[2.2.2]octane derivatives was synthesized and evaluated as long chain fatty acid elongase 6 (ELOVL6) inhibitors. Screening of our corporate chemical collections against ELOVL6 resulted in the identification of lead 1. Exploratory chemistry efforts were applied to lead 1...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2009-08, Vol.17 (15), p.5639-5647
Main Authors: Sasaki, Takahide, Nagase, Tsuyoshi, Takahashi, Toshiyuki, Nagumo, Akira, Shimamura, Ken, Miyamoto, Yasuhisa, Kitazawa, Hidefumi, Kanesaka, Maki, Yoshimoto, Ryo, Aragane, Katsumi, Tokita, Shigeru, Sato, Nagaaki
Format: Article
Language:English
Subjects:
2-Azabicyclo[2.2.2]octane
Acetyltransferases - antagonists & inhibitors
Acetyltransferases - metabolism
Animals
Anti-diabetic agent
Azabicyclo Compounds - chemical synthesis
Azabicyclo Compounds - chemistry
Azabicyclo Compounds - pharmacokinetics
Azabicyclo Compounds - pharmacology
Biological and medical sciences
Fatty Acids - metabolism
General and cellular metabolism. Vitamins
Humans
Lipogenesis
Liver - enzymology
Long chain fatty acid elongase 6 inhibitor
Male
Medical sciences
Mice
Mice, Inbred C57BL
Octanes - chemical synthesis
Octanes - chemistry
Octanes - pharmacokinetics
Octanes - pharmacology
Pharmacology. Drug treatments
Structure-Activity Relationship
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Summary:A series of novel 2-azabicyclo[2.2.2]octane derivatives was synthesized and evaluated as long chain fatty acid elongase 6 (ELOVL6) inhibitors. Screening of our corporate chemical collections against ELOVL6 resulted in the identification of lead 1. Exploratory chemistry efforts were applied to lead 1 to identify the orally available, potent, and selective ELOVL6 inhibitor 28a.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2009.06.042