ASM-IN-1

ASM-IN-1 is a potent and orally active acid sphingomyelinase (ASM) inhibitor with an IC50 value of 1.5 µM. ASM-IN-1 reduces lipid plaques in the aortic arch and aorta and reduces plasma ceramide concentration and Ox-LDL levels. ASM-IN-1 shows antiatherosclerotic and anti-inflammatory activity.

ASM-IN-1 (compound 4i) (0-20 µM) dose not affect cell growth in HUVECs^[1].
ASM-IN-1 (0, 1, 5 µM) reduces the expressions of IL-6 and TNF-α with LPS stimulated in a dose-dependent manner, decreases the expression of MCP-1 mRNA in HUVECs^[1].
ASM-IN-1 (5 µM) reduces Ox-LDL-stimulated MCP-1 mRNA expression and restore IL-6 mRNA to a normal level^[1].

ASM-IN-1 (1 mg/kg for i.v.; 10 mg/kg for p.o.) shows good pharmacokinetic properties with good oral bioavailability of 35.42% in ICR mice^[1].
ASM-IN-1 (6, 12, 40 mg/kg; i.p.; twice a day for 8 weeks) antiatherosclerotic activity by inhibiting ASM in mice^[1].
Pharmacokinetic Parameters of ASM-IN-1 in ICR mice^[1].

parameter	iv	po
T1/2 (h)	0.20 ± 0.04	0.83 ± 0.32
Tmax (h)	0.083 ± 0.00	0.083 ± 0.00
Cmax (ng/mL)	787 ± 64.7	2763 ± 485
AUC0-t (h·ng/mL)	227 ± 14.3	805 ± 76.7
AUC0-∞ (h·ng/mL)	228 ± 15.1	809 ± 75.1
Vz (mL/kg)	1277 ± 216
CL (mL/h/kg)	4390 ± 291
MRT0-t (h)	0.077 ± 0.012	0.32 ± 0.078
MRT0-∞ (h)	0.087 ± 0.019	0.35 ± 0.064
F (%)		35.42 ± 0.033%

ICR mice, 1 mg/kg iv ; 10 mg/kg po^[1]

References:
[1]. Yang K, et al. Discovery of Novel N-Hydroxy-1,2,4-oxadiazole-5-formamides as ASM Direct Inhibitors for the Treatment of Atherosclerosis. J Med Chem. 2023 Feb 23;66(4):2681-2698.