Benzoxazolone carboxamides as potent acid ceramidase inhibitors: Synthesis and structure-activity relationship (SAR) studies

TY - JOUR

T1 - Benzoxazolone carboxamides as potent acid ceramidase inhibitors: Synthesis and structure-activity relationship (SAR) studies

AU - Bach, Anders

AU - Bach, A.; Pizzirani, D.; Realini, N.; Vozella, V.; Russo, D.; Penna, I.; Melzig, L.; Scarpelli, R.; Piomelli, D. (Shared 1st authors)

PY - 2015/12/10

Y1 - 2015/12/10

N2 - 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.

AB - 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.

U2 - 10.1021/acs.jmedchem.5b01188

DO - 10.1021/acs.jmedchem.5b01188

M3 - Journal article

C2 - 26560855

SN - 0022-2623

VL - 58

SP - 9258

EP - 9272

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 23

ER -