Lead Optimization of Benzoxazolone Carboxamides as Orally Bioavailable and CNS Penetrant Acid Ceramidase Inhibitors

  • J Med Chem. 2020 Apr 9;63(7):3634-3664. doi: 10.1021/acs.jmedchem.9b02004.
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 ,  Duc Nguyen  1 ,  Ying Sun  2 ,  Ernesto R Bongarzone  1 ,  Peter Lansbury  3 ,  Min Liu  3 ,  Renato Skerlj  3 ,  Rita Scarpelli
Affiliations
  • 1. The Myelin Regeneration Group at the Dept. Anatomy & Cell Biology, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, 60612, United States.
  • 2. The Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, United States.
  • 3. Lysosomal Therapeutics Inc., 19 Blackstone Street, Cambridge, Massachusetts 02139, United States.
PMID: 32176488 DOI: 10.1021/acs.jmedchem.9b02004
Abstract

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.

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