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Optimization of alpha-ketooxazole 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

  • Kimball, F. S.
  • Romero, F. A.
  • Ezzili, C.
  • Garfunkle, Joie
  • Rayl, T. J.
  • Hochstatter, D. G.
  • Hwang, I.
  • Boger, Dale

publication date

  • 2008

journal

  • Journal of Medicinal Chemistry  Journal

abstract

  • A series of alpha-ketooxazoles containing conformational constraints in the flexible C2 acyl side chain of 2 (OL-135) and representative oxazole C5 substituents were prepared and examined as inhibitors of fatty acid amide hydrolase (FAAH). Exceptionally potent and selective FAAH inhibitors emerged from the series (e.g., 6, Ki = 200 and 260 pM for rat and rhFAAH). With simple and small C5 oxazole substituents, each series bearing a biphenylethyl, phenoxyphenethyl, or (phenoxymethyl)phenethyl C2 side chain was found to follow a well-defined linear relationship between -log Ki and Hammett sigmap of a magnitude (rho = 2.7-3.0) that indicates that the substituent electronic effect dominates, confirming its fundamental importance to the series and further establishing its predictive value. Just as significantly, the nature of the C5 oxazole substituent substantially impacts the selectivity of the inhibitors whereas the effect of the C2 acyl chain was more subtle but still significant even in the small series examined. Combination of these independent features, which display generalized trends across a range of inhibitor series, simultaneously improves FAAH potency and selectivity and can provide exquisitely selective and potent FAAH inhibitors.

subject areas

  • Amidohydrolases
  • Animals
  • Biphenyl Compounds
  • Humans
  • Molecular Conformation
  • Oxazoles
  • Phenyl Ethers
  • Rats
  • Recombinant Proteins
  • Structure-Activity Relationship
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Identity

PubMed Central ID

  • PMC2734917

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm701210y

PubMed ID

  • 18247553
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Additional Document Info

start page

  • 937

end page

  • 947

volume

  • 51

issue

  • 4

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