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

J Med Chem. 2018 Apr 26;61(8):3609-3625. doi: 10.1021/acs.jmedchem.8b00107. Epub 2018 Apr 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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