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

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.