Optimization of α-Ketooxazole Inhibitors of Fatty Acid Amide Hydrolase

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.

X-ray Crystallographic Analysis of α-Ketoheterocycle Inhibitors Bound to a Humanized Variant of Fatty Acid Amide Hydrolase

“…gauche vs extended binding of oleyl side chain) offsets potential gains in inhibitor binding derived from their increased size (length). The systematic examination of the terminal phenyl group placement defined that a linking chain length of 5–6 methylenes is optimal for inhibitors such as 1 – 3 , that the biphenylethyl side chain of 4 typically further improves on this, and that terminal phenyl group removal substantially reduces affinity 30,32,36,37,45. Finally and consistent with the hydrophobic nature of the protein in this linking region, introduction of polar atoms into the linker progressively reduces inhibitor affinity (CH 2 > S > O > NMe > CH(OH) > SO > SO 2 > CONH) 36…”

Therapeutic Potential of Fatty Acid Amide Hydrolase, Monoacylglycerol Lipase, and N-Acylethanolamine Acid Amidase Inhibitors

“…63, 64 The five-membered ring of 12 was also modified by introducing additional heteroatoms. 1,2,4-Oxadiazoles 24 and 25 (Ki = 0.34 nM and 1.1 nM, respectively, Figure 12d) and 1,3,4-oxadiazole 26 (Ki = 0.29 nM, Figure 12d) showed dramatically enhanced inhibition with respect to 12.…”

Approximating Protein Flexibility through Dynamic Pharmacophore Models: Application to Fatty Acid Amide Hydrolase (FAAH)

“…There is also crystallographic evidence that certain α-ketoheterocycle-based FAAH inhibitors form hydrogen bonds from the meta substituent on the pyridine ring to both Cys269 NH and Val270 NH (PDB IDs: 3K7F and 3K83). 15,22,52 …”