α-Ketoheterocycle Inhibitors of Fatty Acid Amide Hydrolase: Exploration of Conformational Constraints in the Acyl Side Chain

Katharine K Duncan, Katerina Otrubova, Dale L Boger

Bioorg Med Chem. 2014 May 1;22(9):2763-70.

PMID: 24690529

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.

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