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
| Autor: | Xian-Cheng Jiang, Deyong Ye, Yong Chu, Yu Cao, Mo Mingguang, Fei Jinyu, Lu Zhou, Yang Chen, Qi Xiangyu, Yang Jintong |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Male Models Molecular Protein Conformation Transferases (Other Substituted Phosphate Groups) Sphingomyelin synthase activity Inflammation Nerve Tissue Proteins Pharmacology Diabetes Mellitus Experimental 03 medical and health sciences Mice Structure-Activity Relationship 0302 clinical medicine Pharmacokinetics In vivo Drug Discovery medicine Potency Structure–activity relationship Animals Humans Amines Enzyme Inhibitors Mice Inbred ICR Molecular Structure Chemistry Membrane Proteins In vitro Bioavailability 030104 developmental biology 030220 oncology & carcinogenesis Molecular Medicine medicine.symptom |
| Zdroj: | Journal of medicinal chemistry. 61(18) |
| ISSN: | 1520-4804 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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