Thermodynamic and structure guided design of statin based inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase.
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 (IC 50 = 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 Delta H 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.
Pfizer Global Research & Development, Ann Arbor, Michigan 48105, USA. Ronald.w.sarver@pfizer.com
Ronald W
RW
Sarver
Elizabeth
E
Bills
Gary
G
Bolton
Larry D
LD
Bratton
Nicole L
NL
Caspers
James B
JB
Dunbar
Melissa S
MS
Harris
Richard H
RH
Hutchings
Robert M
RM
Kennedy
Scott D
SD
Larsen
Alexander
A
Pavlovsky
Jeffrey A
JA
Pfefferkorn
Graeme
G
Bainbridge
D000818:Animals; D001665:Binding Sites; D002151:Calorimetry; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D015195:Drug Design; D005464:Fluorobenzenes / Q000737:chemistry / Q000494:pharmacology; D022781:Hepatocytes / Q000187:drug effects / Q000201:enzymology; D006903:Hydroxymethylglutaryl CoA Reductases / Q000737:chemistry* / Q000378:metabolism*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D007093:Imidazoles / Q000737:chemistry / Q000494:pharmacology; D051379:Mice; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008958:Models, Molecular; D015394:Molecular Structure; D032342:Muscle Cells / Q000187:drug effects / Q000201:enzymology; D011743:Pyrimidines / Q000737:chemistry / Q000494:pharmacology; D011758:Pyrroles / Q000737:chemistry / Q000494:pharmacology; D051381:Rats; D000068718:Rosuvastatin Calcium; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D013816:Thermodynamics
D005464:Fluorobenzenes; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D007093:Imidazoles; D011743:Pyrimidines; D011758:Pyrroles; D013449:Sulfonamides; D000068718:Rosuvastatin Calcium; D006903:Hydroxymethylglutaryl CoA Reductases