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

Eleonora Diamanti; Giovanni Bottegoni; Luca Goldoni; Natalia Realini; Chiara Pagliuca; Fabio Bertozzi; Daniele Piomelli; Daniela Pizzirani

doi:10.1055/s-0035-1561456

Synthesis, Table of Contents

Synthesis 2016; 48(17): 2739-2756
DOI: 10.1055/s-0035-1561456

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

Eleonora Diamanti

^aDrug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy

,

Giovanni Bottegoni

^aDrug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy

,

Luca Goldoni

^aDrug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy

,

Natalia Realini

^aDrug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy

,

Chiara Pagliuca

^aDrug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy

,

Fabio Bertozzi

^aDrug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy

,

Daniele Piomelli*

^aDrug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy

^bDepartments of Anatomy and Neurobiology, Pharmacology and Biological Chemistry, University of California, Irvine, CA 92697, USA Email: daniele.piomelli@iit.it

,

Daniela Pizzirani

^aDrug Discovery and Development, Fondazione Istituto Italiano di Tecnologia, via Morego 30, 16163 Genova, Italy

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Abstract

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

Key words

acid ceramidase - ceramides - atomic property field (APF) - regioisomers - structure–activity relationship (SAR) - melanoma

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References

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