Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 61, Issue 8, Pages 3609-3625Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.8b00107
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Funding
- National Natural Science Foundation of China [81773614]
- Key Research Program of the Chinese Academy of Sciences [KFZD-SW-219]
- Strategic Biological Resources Service Network Programme of CAS [ZSTH-016]
- Youth Innovation Promotion Association of CAS [2014074]
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It is a great challenge to develop drugs for treatment of metabolic syndrome. With ganomycin I as a leading compound, 14 meroterpene derivatives were synthesized and screened for their a-glucosidase and HMG-CoA reductase inhibitory activities. As a result, a a-glucosidase and HMG-CoA reductase dual inhibitor ((R,E)-5-(4-(tert-butyl)pheny1)-3-(4,8dimethylnona-3,7-dien-1-y0furan-2(5H)-one, 7d) with improved chemical stability and long-term safety was obtained. Compound 7d showed multiple and strong in vivo efficacies in reducing weight gain, lowering HbAlc level, and improving insulin resistance and lipid dysfunction in both ob/ob and diet-induced obesity (DIO) mice models. Compound 7d was also found to reduce hepatic steatosis in ob/ob model. 16S rRNA gene sequencing, SCFA, and intestinal mucosal barrier function analysis indicated that gut microbiota plays a central and causative role in mediating the multiple efficacies of 7d. Our results demonstrate that 7d is a promising drug candidate for metabolic syndrome.
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