ABSTRACT
The design of drugs with selective tissue distribution can be an effective strategy for enhancing efficacy and safety, but understanding the translation of preclinical tissue distribution data to the clinic remains an important challenge. As part of a discovery program to identify next generation liver selective HMG-CoA reductase inhibitors we report the identification of (3R,5R)-7-(4-((3-fluorobenzyl)carbamoyl)-5-cyclopropyl-2-(4-fluorophenyl)-1H-imidazol-1-yl)-3,5-dihydroxyheptanoic acid (26) as a candidate for treating hypercholesterlemia. Clinical evaluation of 26 (PF-03491165), as well as the previously reported 2 (PF-03052334), provided an opportunity for a case study comparison of the preclinical and clinical pharmacokinetics as well as pharmacodynamics of tissue targeted HMG-CoA reductase inhibitors.
Subject(s)
Drug Discovery , Heptanoic Acids/chemical synthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemical synthesis , Hypercholesterolemia/drug therapy , Imidazoles/chemical synthesis , Liver/drug effects , Animals , Cells, Cultured , Dogs , Dose-Response Relationship, Drug , Hepatocytes/drug effects , Heptanoic Acids/chemistry , Heptanoic Acids/pharmacokinetics , Heptanoic Acids/pharmacology , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacokinetics , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Imidazoles/chemistry , Imidazoles/pharmacokinetics , Imidazoles/pharmacology , Inhibitory Concentration 50 , Molecular Structure , Pyrazoles/chemical synthesis , Pyrazoles/chemistry , Pyrazoles/pharmacokinetics , Pyrazoles/pharmacology , Rats , Tissue DistributionABSTRACT
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.
Subject(s)
Drug Design , Hydroxymethylglutaryl CoA Reductases/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemistry , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Pyrazoles/chemistry , Pyrazoles/pharmacology , Animals , Cell Line , Cricetinae , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemical synthesis , Liver/drug effects , Liver/enzymology , Molecular Structure , Muscle Cells/drug effects , Muscle Cells/enzymology , Pyrazoles/chemical synthesis , Rats , Structure-Activity RelationshipABSTRACT
Using structure-based design, a novel series of conformationally restricted, pyrrole-based inhibitors of HMG-CoA reductase were discovered. Leading analogs demonstrated potent inhibition of cholesterol synthesis in both in vitro and in vivo models and may be useful for the treatment of hypercholesterolemia and related lipid disorders.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemical synthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Animals , Cholesterol/biosynthesis , Drug Design , Hyperlipidemias/drug therapy , Mice , Molecular Biology , Molecular Structure , Structure-Activity RelationshipABSTRACT
This manuscript describes the design and synthesis of a series of pyrrole-based inhibitors of HMG-CoA reductase for the treatment of hypercholesterolemia. Analogs were optimized using structure-based design and physical property considerations resulting in the identification of 44, a hepatoselective HMG-CoA reductase inhibitor with excellent acute and chronic efficacy in a pre-clinical animal models.
