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Discovery of a new class of highly potent inhibitors of acid ceramidase: synthesis and structure-activity relationship (SAR).

Abstract：

:Acid ceramidase (AC) is an intracellular cysteine amidase that catalyzes the hydrolysis of the lipid messenger ceramide. By regulating ceramide levels in cells, AC may contribute to the regulation of cancer cell proliferation and senescence and to the response to cancer therapy. We recently identified the antitumoral agent carmofur (4a) as the first nanomolar inhibitor of intracellular AC activity (rat AC, IC50 = 0.029 μM). In the present work, we expanded our initial structure-activity relationship (SAR) studies around 4a by synthesizing and testing a series of 2,4-dioxopyrimidine-1-carboxamides. Our investigations provided a first elucidation of the structural features of uracil derivatives that are critical for AC inhibition and led us to identify the first single-digit nanomolar inhibitors of this enzyme. The present results confirm that substituted 2,4-dioxopyrimidine-1-carboxamides are a novel class of potent inhibitors of AC. Selected compounds of this class may represent useful probes to further characterize the functional roles of AC.

journal_name

J Med Chem

journal_title

Journal of medicinal chemistry

authors

Pizzirani D,Pagliuca C,Realini N,Branduardi D,Bottegoni G,Mor M,Bertozzi F,Scarpelli R,Piomelli D,Bandiera T

doi

10.1021/jm301879g

subject

Has Abstract

pub_date

2013-05-09 00:00:00

pages

3518-30

issue

9

eissn

0022-2623

issn

1520-4804

journal_volume

56

pub_type

杂志文章

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