MEDI 216 |
| Lowering atherogenic LDL cholesterol in man has been shown to lower the incidence of heart disease and extend lives. While HMG-CoA reductase inhibitors have been particularly effective in this endeavor, they primarily treat endogenously synthesized cholesterol and have little impact on dietary or intestinally derived cholesterol. In our efforts to affect this second source of cholesterol, we discovered a novel class of β-lactam cholesterol absorption inhibitors that operated via an unknown mechanism. Optimization of the in vivo SAR lead to the discovery of our first clinical candidate, SCH 48461. A close examination of the metabolism of this compound revealed an important oxidative metabolite with greatly improved potency. Incorporation of this “positive metabolism” and blocking additional sites led to the discovery of ezetimibe. Ezetimibe is the first molecular entity approved for use as a cholesterol absorption inhibitor alone or in combination with statins to treat hypercholesterolemia. |
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Heroes of Chemistry
1:30 PM-5:00 PM, Monday, August 20, 2007 BCEC -- 210 B/C, Oral
Division of Medicinal Chemistry |