Benzoxazolone Carboxamides as Potent Acid Ceramidase Inhibitors: Synthesis and Structure–Activity Relationship (SAR) Studies

Ceramides are lipid-derived intracellular
messengers involved in
the control of senescence, inflammation, and apoptosis. The cysteine
amidase, acid ceramidase (AC), hydrolyzes these substances into sphingosine
and fatty acid and, by doing so, regulates their signaling activity.
AC inhibitors may be useful in the treatment of pathological conditions,
such as cancer, in which ceramide levels are abnormally reduced. Here,
we present a systematic SAR investigation of the benzoxazolone carboxamides,
a recently described class of AC inhibitors that display high potency
and systemic activity in mice. We examined a diverse series of substitutions
on both benzoxazolone ring and carboxamide side chain. Several modifications
enhanced potency and stability, and one key compound with a balanced
activity–stability profile (14) was found to inhibit
AC activity in mouse lungs and cerebral cortex after systemic administration.
The results expand our arsenal of AC inhibitors, thereby facilitating
the use of these compounds as pharmacological tools and their potential
development as drug leads.