2. Academic Validation
  3. α-Ketoheterocycle inhibitors of fatty acid amide hydrolase: exploration of conformational constraints in the acyl side chain

α-Ketoheterocycle inhibitors of fatty acid amide hydrolase: exploration of conformational constraints in the acyl side chain

  • Bioorg Med Chem. 2014 May 1;22(9):2763-70. doi: 10.1016/j.bmc.2014.03.013.
Katharine K Duncan 1,  Katerina Otrubova 1,  Dale L Boger 2
Affiliations

Affiliations

  • 1 Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States.
  • 2 Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, United States. Electronic address: boger@scripps.edu.
PMID: 24690529 DOI: 10.1016/j.bmc.2014.03.013
Abstract

A series of α-ketooxazoles containing heteroatoms embedded within conformational constraints in the C2 acyl side chain of 2 (OL-135) were synthesized and evaluated as inhibitors of fatty acid amide hydrolase (FAAH). The studies reveal that the installation of a heteroatom (O) in the conformational constraint is achievable, although the potency of these novel derivatives is reduced slightly relative to 2 and the analogous 1,2,3,4-tetrahydronaphthalene series. Interestingly, both enantiomers (R and S) of the candidate inhibitors bearing a chiral center adjacent to the electrophilic carbonyl were found to effectively inhibit FAAH.

Keywords

Fatty acid amide hydrolase; α-Ketoheterocycles.

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