Thermodynamic and Structure Guided Design of Statin Based Inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase

详细信息    查看全文

• 作者：Ronald W. Sarver ; Elizabeth Bills ; Gary Bolton ; Larry D. Bratton ; Nicole L. Caspers ; James B. Dunbar ; Melissa S. Harris ; Richard H. Hutchings ; Robert M. Kennedy ; Scott D. Larsen ; Alexander Pavlovsky
• 刊名：Journal of Medicinal Chemistry
• 出版年：2008
• 出版时间：July 10, 2008
• 年：2008
• 卷：51
• 期：13
• 页码：3804 - 3813
• 全文大小：1573K
• 年卷期：v.51,no.13(July 10, 2008)
• ISSN：1520-4804

文摘

Clinical studies have demonstrated that statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR) inhibitors, are effective at lowering mortality levels associated with cardiovascular disease; however, 2–7% of patients may experience statin-induced myalgia that limits compliance with a treatment regimen. High resolution crystal structures, thermodynamic binding parameters, and biochemical data were used to design statin inhibitors with improved HMGR affinity and therapeutic index relative to statin-induced myalgia. These studies facilitated the identification of imidazole 1 as a potent (IC₅₀ = 7.9 nM) inhibitor with excellent hepatoselectivity (>1000-fold) and good in vivo efficacy. The binding of 1 to HMGR was found to be enthalpically driven with a ΔH of –17.7 kcal/M. Additionally, a second novel series of bicyclic pyrrole-based inhibitors was identified that induced order in a protein flap of HMGR. Similar ordering was detected in a substrate complex, but has not been reported in previous statin inhibitor complexes with HMGR.