依替米贝.ppt

The discovery and synthesis of ezetimibe
CONTENT
INTRODUCTION
THE DISCOVERY OF EZETIMIBE
THE SYNTHESIS OF EZETIMIBE
High blood-cholesterol levels constitute a major risk factor for cardiovascular disease, the leading cause of death in the Western industrialized total blood cholesterol level is primarily regulated by plementary mechanisms: (1) cholesterol biosynthesis in the liver and (2) absorption of dietary cholesterol in the small intestine. Since their introduction in the late 1980s, statins have by far e the predominant class of current lipid-lowering drugs (96% of total sales in 2001). Statins inhibit HMG-CoA reductase, the enzyme that catalyzes the rate-limiting step of cholesterol biosynthesis in the , the patient response to statins varies greatly, with half of all patients on statin therapies failing to reach their cholesterol goals. Ezetimibe, which was approved in late 2002 for use either alone and bination with a statin, is the only example to date of a drug that involves inhibition of intestinal cholesterol absorption.
preface
INTRODUCTION
THE DISCOVERY OF EZETIMIBE
THE SYNTHESIS OF EZETIMIBE
zetia(Ezetimibe)
(1-(4-fluorophenyl)-(3R)-[3-(4-fluorophenyl)-(3S)-hydroxypropyl]-(4S)-(4-hydroxyphenyl)-2-azetidinone
SCH 58235(found by Merck and Schering-Plough)
2002 published in Germany, 2007 in China
first of the cholesterol absorption inhibitors, inhibit the absorption of biliary and dietary cholesterol from the small intestine without affecting the absorption of fat-soluble vitamins, triglycerides or bile acids
Ezetimibe reduces the small intestinal enterocyte uptake and absorption of cholesterol by binding to Niemann-Pick C1 Like 1 (NPC1L1)
1, introduction
Biotransformation pathway for ezetimibe in humans and animals
cholesterol metabolism
2D view of the NPC1 topology
Hypothetical NPC1 membrane arrangement. Basedon the topology of NPC1 and its similarity to prokaryotic molecular pumps, NPC1 may act in a similar manne