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α-Ketoheterocycle-based inhibitors of Fatty Acid Amide Hydrolase (FAAH)

Academic Article
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Overview

related to degree

  • Otrubova, Katerina, Ph.D. in Chemistry, Scripps Research 2007 - 2013

authors

  • Otrubova, Katerina
  • Boger, Dale

publication date

  • May 2012

journal

  • ACS Chemical Neuroscience  Journal

abstract

  • A summary of the initial discovery and characterization of the enzyme fatty acid amide hydrolase (FAAH), and the subsequent advancement of an important class of competitive, reversible, potent and selective inhibitors is presented. Initially explored using substrate-inspired inhibitors bearing electrophilic carbonyls, the examination of α-ketoheterocyle-based inhibitors of FAAH with the benefit of a unique activity-based protein-profiling (ABPP)-based proteome-wide selectivity assay, a powerful in vivo biomarker-based in vivo screen, and subsequent retrospective X-ray co-crystal structures with the enzyme, is summarized. These efforts defined the impact of the central activating heterocycle and its key substituents, provided key simplifications in the C2 acyl side chain and clear interpretations for the unique role and subsequent optimization of the central activating heterocycle, and established the basis for the recent further conformational constraints in the C2 acyl side chain, providing potent, long-acting, orally-active FAAH inhibitors.
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Research

keywords

  • FAAH
  • Fatty acid amide hydrolase
  • alpha-ketoheterocycles
  • pain
  • sleep
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Identity

PubMed Central ID

  • PMC3359644

International Standard Serial Number (ISSN)

  • 1948-7193

Digital Object Identifier (DOI)

  • 10.1021/cn2001206

PubMed ID

  • 22639704
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Additional Document Info

start page

  • 340

end page

  • 348

volume

  • 3

issue

  • 5

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