当前位置： SCI文献检索 > JOURNAL OF MEDICINAL CHEMISTRY期刊下所有文献 > SAR and LC/MS studies of β-lactamic inhibitors of human fatty acid amide hydrolase (hFAAH): evidence of a nonhydrolytic process.

SAR and LC/MS studies of β-lactamic inhibitors of human fatty acid amide hydrolase (hFAAH): evidence of a nonhydrolytic process.

Abstract：

:The endocannabinoid hydrolyzing enzyme FAAH uses a nonclassical catalytic triad (namely, Ser-Ser-Lys instead of Ser-Asp-His) to cleave its endogenous substrates. Because inhibiting FAAH has a clear therapeutic potential, we previously developed β-lactam-type inhibitors of hFAAH. Here, we report the synthesis of five novel derivatives (5-9) of our lead compound 1-(pent-4-enoyl)-3(S)-[1(R)-(4-phenylbutanoyloxy)-ethyl]-azetidin-2-one (4, IC(50) = 5 nM) obtained via the systematic replacement of one to three carbonyls by methylene groups. The SAR results showed that the imide, but not the lactam, function is essential to the inhibition of hFAAH. We also performed LC/MS analysis following incubation of our inhibitors with hFAAH or mouse liver. We demonstrated that hFAAH interacts with these β-lactam-type inhibitors but, unexpectedly, does not open the β-lactam moiety. This mechanism seems to be unique to FAAH because the β-lactam function of the inhibitors is hydrolyzed when they are incubated in the presence of the serine hydrolases expressed in the mouse liver. Finally, we confirmed these results by showing that a highly selective FAAH inhibitor (PF-750) does not prevent this hydrolysis by liver homogenates.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Feledziak M,Muccioli GG,Lambert DM,Marchand-Brynaert J

doi

10.1021/jm200723m

subject

Has Abstract

pub_date

2011-10-13 00:00:00

pages

6812-23

issue

19

eissn

0022-2623

issn

1520-4804

journal_volume

54

pub_type

杂志文章

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