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Optimization of the central heterocycle of alpha-ketoheterocycle inhibitors of fatty acid amide hydrolase

Academic Article
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Overview

related to degree

  • Garfunkle, Joie, Ph.D. in Chemistry, Scripps Research 2004 - 2009

authors

  • Garfunkle, Joie
  • Ezzili, C.
  • Rayl, T. J.
  • Hochstatter, D. G.
  • Hwang, I.
  • Boger, Dale

publication date

  • August 2008

journal

  • Journal of Medicinal Chemistry  Journal

abstract

  • The synthesis and evaluation of a refined series of alpha-ketoheterocycles based on the oxazole 2 (OL-135) incorporating systematic changes in the central heterocycle bearing a key set of added substituents are described. The nature of the central heterocycle, even within the systematic and minor perturbations explored herein, significantly influenced the inhibitor activity: 1,3,4-oxadiazoles and 1,2,4-oxadiazoles 9 > tetrazoles, the isomeric 1,2,4-oxadiazoles 10, 1,3,4-thiadiazoles > oxazoles including 2 > 1,2-diazines > thiazoles > 1,3,4-triazoles. Most evident in these trends is the observation that introduction of an additional heteroatom at position 4 (oxazole numbering, N > O > CH) substantially increases activity that may be attributed to a reduced destabilizing steric interaction at the FAAH active site. Added heterocycle substituents displaying well-defined trends may be utilized to enhance the inhibitor potency and, more significantly, to enhance the inhibitor selectivity. These trends, exemplified herein, emerge from both enhancements in the FAAH activity and simultaneous disruption of binding affinity for competitive off-target enzymes.

subject areas

  • Amidohydrolases
  • Animals
  • Azoles
  • COS Cells
  • Cercopithecus aethiops
  • Electrons
  • Enzyme Inhibitors
  • Escherichia coli
  • Heterocyclic Compounds
  • Humans
  • Isomerism
  • Methylation
  • Molecular Structure
  • Oxazoles
  • Recombinant Proteins
  • Structure-Activity Relationship
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Identity

PubMed Central ID

  • PMC2556205

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm800136b

PubMed ID

  • 18630870
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Additional Document Info

start page

  • 4392

end page

  • 4403

volume

  • 51

issue

  • 15

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