Discovery of 4-Benzyloxybenzo[d]isoxazole-3-amine Derivatives as Highly Selective and Orally Efficacious Human Sphingomyelin Synthase 2 Inhibitors that Reduce Chronic Inflammation in db/db Mice

Abstract

Sphingomyelin synthase 2 (SMS2) is a promising therapeutic target for several chronic inflammation-associated diseases, including atherosclerosis, fatty liver, and insulin resistance. Herein, we report the identification of 4-benzyloxybenzo[ d]isoxazole-3-amine derivatives as potent and highly selective SMS2 inhibitors through a conformational restriction strategy. After systematic structural modifications, several compounds with high selectivity and good potency in vitro were selected for further evaluation. Compound 15w demonstrated good pharmacokinetics (oral bioavailability, F = 56%) in vivo and has an inhibitory potency against sphingomyelin synthase activity when Institute of Cancer Research mice are provided with an oral dose of this compound. In addition, compound 15w attenuated chronic inflammation significantly in db/ db mice after oral dosing for 6 weeks.

Glucose metabolism enhancement by 10-hydroxy-2-decenoic acidviathe PI3K/AKT signaling pathway in high-fat-diet/streptozotocin induced type 2 diabetic mice

“…T2DM is associated with activation of proinflammatory cytokines. 23 As indicated in Fig. 8, diabetic mice exhibited an inflammatory response, which mainly manifested as increased TNF-α and IL-6 content in the liver, relative to the control group ( P < 0.01); these increases were effectively reduced by 10-HDA treatment ( P < 0.05), clearly demonstrating that 10-HDA can inhibit inflammatory factor release in the liver of diabetic mice.…”

Liver sphingomyelin synthase 1 deficiency causes steatosis, steatohepatitis, fibrosis, and tumorigenesis: An effect of glucosylceramide accumulation

“…Importantly, normal liver GluCer levels are observed in the setting of SMS2 deficiency ( Li et al., 2012 ). Thus, we and others have suggested that SMS2 could be a therapeutic target for human metabolic diseases ( Li et al., 2019 ; Mo et al., 2018 ; Sugimoto et al., 2016 ). In contrast, mice with global SMS1 deficiency exhibit moderate neonatal lethality ( Li et al., 2012 ; Yano et al., 2011 ), as more than 30% of homozygous Sms 1 global KO mice die postnatally (the remainder can grow to adulthood).…”

Ceramide/Sphingomyelin Rheostat Regulated by Sphingomyelin Synthases and Chronic Diseases in Murine Models

“…Indeed, recent studies have shown the development of novel SMS2 inhibitors to suppress these inflammatory diseases in mouse model. 138 139 140 Therefore, SMS2 is strongly suggested as a potential target to develop drugs for acute phase inflammation and cancers.…”