Synthesis 2016; 48(17): 2739-2756
DOI: 10.1055/s-0035-1561456
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© Georg Thieme Verlag Stuttgart · New York

Pyrazole-Based Acid Ceramidase Inhibitors: Design, Synthesis, and Structure–Activity Relationships

Eleonora Diamanti
a  Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
,
Giovanni Bottegoni
a  Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
,
Luca Goldoni
a  Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
,
Natalia Realini
a  Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
,
Chiara Pagliuca
a  Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
,
Fabio Bertozzi
a  Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
,
Daniele Piomelli*
a  Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
b  Departments of Anatomy and Neurobiology, Pharmacology and Biological Chemistry, University of California, Irvine, CA 92697, USA   Email: daniele.piomelli@iit.it
,
Daniela Pizzirani
a  Drug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy
› Author Affiliations
Further Information

Publication History

Received: 24 February 2016

Accepted after revision: 18 April 2016

Publication Date:
09 June 2016 (online)


Dedicated to Professor Stuart L. Schreiber on the occasion of his 60th birthday

Abstract

Acid ceramidase (AC) is a lysosomal cysteine amidase responsible for the cleavage of ceramide into sphingosine, which is then phosphorylated to sphingosine 1-phosphate. AC regulates the intracellular levels of ceramide and sphingosine, and AC inhibition may be useful in the treatment of disorders, such as cancer, in which ceramide-mediated­ signaling may be dysfunctional. Despite their potential experimental and therapeutic value, the number of available small-molecule inhibitors of AC activity remains limited. In the present study is described the discovery of a class of potent pyrazole carboxamide-based AC inhibitors, which were identified using the atomic property field (APF) approach and developed through systematic SAR investigations and in vitro pharmacological characterization. The best compound of this series inhibits AC with nanomolar potency and causes ceramide accumulation and sphingosine depletion in intact G361 proliferative melanoma cells. By expanding the current armamentarium of AC inhibitors, these results should facilitate future efforts to unravel the biology of AC and the therapeutic potential of its inhibition.

Supporting Information

 
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