Thermodynamic and Structure Guided Design of Statin Based Inhibitors of 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase.
作者
Sarver, Ronald W.;Bills, Elizabeth;Bolton, Gary;Bratton, Larry D.;Caspers, Nicole L.;Dunbar, James B.;Harris, Melissa S.;Hutchings, Richard H.;Kennedy, Robert M.;Larsen, Scott D.;Pavlovsky, Alexander;Pfefferkorn, Jeffrey A.;Bainbridge, Graeme;
[摘要]：Clin. studies have demonstrated that statins, 3-hydroxy-3-methylglutaryl CoA reductase (HMGR) inhibitors, are effective at lowering mortality levels assocd. with cardiovascular disease; however, 2-7% of patients may experience statin-induced myalgia that limits compliance with a treatment regimen. High resoln. crystal structures, thermodn. binding parameters, and biochem. 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 enthalpically driven with a DH of -17.7 kcal/M. Addnl., 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.
