Structural Modification of Natural Product Ganomycin I Leading to Discovery of a α-Glucosidase and HMG-CoA Reductase Dual Inhibitor Improving Obesity and Metabolic Dysfunction in Vivo.

Abstract

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 α-glucosidase and HMG-CoA reductase inhibitory activities. As a result, a α-glucosidase and HMG-CoA reductase dual inhibitor (( R, E)-5-(4-( tert-butyl)phenyl)-3-(4,8-dimethylnona-3,7-dien-1-yl)furan-2(5 H)-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.

• Authors: Kai Wang, Li Bao, Nan Zhou, Jinjin Zhang, Mingfang Liao, Zhongyong Zheng, Yujing Wang, Chang Liu, Jun Wang, Lifeng Wang, Wenzhao Wang, ShuangJiang Liu, Hongwei Liu
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 61 Issue 8 Pg. 3609-3625 (04 26 2018) ISSN: 1520-4804 [Electronic] United States
• PMID: 29634260 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Anti-Obesity Agents
• Glycoside Hydrolase Inhibitors
• Hydroxymethylglutaryl-CoA Reductase Inhibitors
• Lactones
• Terpenes
• Hydroxymethylglutaryl CoA Reductases
• alpha-Glucosidases

Topics

• Animals
• Anti-Obesity Agents (chemical synthesis, pharmacokinetics, therapeutic use, toxicity)
• Drug Stability
• Fatty Liver (drug therapy)
• Female
• Gastrointestinal Microbiome (drug effects)
• Glycoside Hydrolase Inhibitors (chemical synthesis, pharmacokinetics, therapeutic use, toxicity)
• Hydroxymethylglutaryl CoA Reductases (metabolism)
• Hydroxymethylglutaryl-CoA Reductase Inhibitors (chemical synthesis, pharmacokinetics, therapeutic use, toxicity)
• Lactones (chemical synthesis, pharmacokinetics, therapeutic use, toxicity)
• Male
• Metabolic Syndrome (drug therapy)
• Mice, Inbred C57BL
• Microsomes, Liver (metabolism)
• Obesity (drug therapy)
• Rats, Sprague-Dawley
• Swine
• Terpenes (chemical synthesis, pharmacokinetics, therapeutic use, toxicity)
• alpha-Glucosidases (metabolism)