ABSTRACT
In light of accumulating evidence that aggressive LDL-lowering therapy may offer increased protection against coronary heart disease, we undertook the design and synthesis of a novel series of HMG-CoA reductase inhibitors based upon a substituted pyrazole template. Optimizing this series using both structure-based design and molecular property considerations afforded a class of highly efficacious and hepatoselective inhibitors resulting in the identification of (3 R,5 R)-7-[2-(4-fluoro-phenyl)-4-isopropyl-5-(4-methyl-benzylcarbamoyl)-2 H-pyrazol-3-yl]-3,5-dihydroxy-heptanoic (PF-3052334) as a candidate for the treatment of hypercholesterolemia.
Subject(s)
Heptanoic Acids/chemical synthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemical synthesis , Hypercholesterolemia/drug therapy , Liver/drug effects , Pyrazoles/chemical synthesis , Animals , Cholesterol, LDL/biosynthesis , Cholesterol, LDL/blood , Cricetinae , Guinea Pigs , Hepatocytes/drug effects , Hepatocytes/metabolism , Heptanoic Acids/chemistry , Heptanoic Acids/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemistry , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , In Vitro Techniques , Liver/metabolism , Male , Mesocricetus , Muscle Cells/drug effects , Muscle Cells/metabolism , Pyrazoles/chemistry , Pyrazoles/pharmacology , Rats , Stereoisomerism , Structure-Activity RelationshipABSTRACT
4-Sulfamoyl pyrroles were designed as novel hepatoselective HMG-CoA reductase inhibitors (statins) to reduce myalgia, a statin-induced adverse effect. The compounds were prepared via a [3+2] cycloaddition of a Münchnone with a sulfonamide-substituted alkyne. We identified compounds with greater selectivity for hepatocytes compared to L6-myocytes than rosuvastatin and atorvastatin. There was an inverse correlation of myocyte potencies and ClogP values. A number of analogs were effective at reducing cholesterol in acute and chronic in vivo models but they lacked sufficient chronic in vivo activity to warrant further development.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemical synthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Muscle Cells/drug effects , Pyrroles/chemical synthesis , Pyrroles/pharmacology , Sulfonamides/chemical synthesis , Sulfonamides/pharmacology , Animals , Atorvastatin , Combinatorial Chemistry Techniques , Disease Models, Animal , Fluorobenzenes/pharmacology , Hepatocytes/drug effects , Heptanoic Acids/pharmacology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemistry , Mice , Molecular Structure , Pyrimidines/pharmacology , Pyrroles/chemistry , Rosuvastatin CalciumABSTRACT
An extraordinarily potent and hepatoselective class of HMG-CoA reductase inhibitors containing a pyrazole core was recently reported; however, its development was hampered by a long and difficult synthetic route. We attempted to circumvent this obstacle by preparing closely related analogs wherein the key dihydroxyheptanoic acid sidechain was tethered to the pyrazole core via an oxygen linker ('oxypyrazoles'). This minor change reduced the total number of synthetic steps from 14 to 7. Although the resulting analogs maintained much of the in vitro and cell activity of the pyrazoles, inferior in vivo activity precluded further development. Caco-2 cell permeability data suggest that enhanced cellular efflux of the oxypyrazoles relative to the pyrazoles may be responsible for the poor in vivo activity.
