Open AccessLead Optimization of Benzoxazolone Carboxamides as Orally Bioavailable and CNS Penetrant Acid Ceramidase Inhibitors
Author(s) -
Simona Di Martino,
Piero Tardia,
Vincenzo Cilibrasi,
Samantha Caputo,
Marco Mazzonna,
Debora Russo,
Ilaria Penna,
Natalia Realini,
Natasha Margaroli,
Marco Migliore,
Daniela Pizzirani,
Giuliana Ottonello,
Sine Mandrup Bertozzi,
Andrea Armirotti,
Duy Anh Nguyễn,
Ying Sun,
Ernesto R. Bongarzone,
Peter T. Lansbury,
Min Liu,
Renato T. Skerlj,
Rita Scarpelli
Publication year - 2020
Publication title -
journal of medicinal chemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.01
H-Index - 261
eISSN - 1520-4804
pISSN - 0022-2623
DOI - 10.1021/acs.jmedchem.9b02004
Subject(s) - chemistry , sphingolipid , enzyme , pharmacology , biochemistry , lead compound , krabbe disease , disease , leukodystrophy , in vitro , medicine , biology
Sphingolipids (SphLs) are a diverse class of molecules that are regulated by a complex network of enzymatic pathways. A disturbance in these pathways leads to lipid accumulation and initiation of several SphL-related disorders. Acid ceramidase is one of the key enzymes that regulate the metabolism of ceramides and glycosphingolipids, which are important members of the SphL family. Herein, we describe the lead optimization studies of benzoxazolone carboxamides resulting in piperidine 22m , where we demonstrated target engagement in two animal models of neuropathic lysosomal storage diseases (LSDs), Gaucher's and Krabbe's diseases. After daily intraperitoneal administration at 90 mg kg -1 , 22m significantly reduced the brain levels of the toxic lipids glucosylsphingosine (GluSph) in 4L;C* mice and galactosylsphingosine (GalSph) in Twitcher mice. We believe that 22m is a lead molecule that can be further developed for the correction of severe neurological LSDs where GluSph or GalSph play a significant role in disease pathogenesis.