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, 50 (14), 3359-68

Structure-activity Relationships of Alpha-Ketooxazole Inhibitors of Fatty Acid Amide Hydrolase

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Structure-activity Relationships of Alpha-Ketooxazole Inhibitors of Fatty Acid Amide Hydrolase

Christophe Hardouin et al. J Med Chem.

Abstract

A systematic study of the structure-activity relationships of 2b (OL-135), a potent inhibitor of fatty acid amide hydrolase (FAAH), is detailed targeting the C2 acyl side chain. A series of aryl replacements or substituents for the terminal phenyl group provided effective inhibitors (e.g., 5c, aryl = 1-napthyl, Ki = 2.6 nM), with 5hh (aryl = 3-ClPh, Ki = 900 pM) being 5-fold more potent than 2b. Conformationally restricted C2 side chains were examined, and many provided exceptionally potent inhibitors, of which 11j (ethylbiphenyl side chain) was established to be a 750 pM inhibitor. A systematic series of heteroatoms (O, NMe, S), electron-withdrawing groups (SO, SO2), and amides positioned within and hydroxyl substitutions on the linking side chain were investigated, which typically led to a loss in potency. The most tolerant positions provided effective inhibitors (12p, 6-position S, Ki = 3 nM, or 13d, 2-position OH, Ki = 8 nM) comparable in potency to 2b. Proteome-wide screening of selected inhibitors from the systematic series of >100 candidates prepared revealed that they are selective for FAAH over all other mammalian serine proteases.

Figures

Figure 1
Figure 1
Substrates of fatty acid amide hydrolase (FAAH).
Figure 2
Figure 2
FAAH Inhibitors.
Figure 3
Figure 3
Preceding studies of the C2 side chain.
Figure 4
Figure 4
Substitution of the C2 side chain terminal phenyl group.
Figure 5
Figure 5
Conformationally restricted C2 side chain inhibitors.
Figure 6
Figure 6
Linker alkynes.
Figure 7
Figure 7
Incorporation of heteroatoms within the side chain.
Figure 8
Figure 8
Hydroxyl and amide substitution.
Figure 9
Figure 9
Effect of additional side chain modifications.
Figure 10
Figure 10
Inhibition of Recombinant Human Fatty Acid Amide Hydrolase.
Figure 11
Figure 11
Selectivity screening; IC50 (selectivity). A full table of results is reported in Supporting Information.
Scheme 1
Scheme 1
Scheme 2
Scheme 2

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