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
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
A series of 1,4-benzyloxybenzylsulfanylaryl carboxylic acids were prepared and their activities for PPAR receptor subtypes (alpha, delta, and gamma) with potential indications for the treatment of dyslipidemia were investigated. Analog 13a displayed the greatest binding affinity (IC(50)=10nM) and selectivity (120-fold) for PPARdelta over PPARalpha. Many of the analogs investigated were found to be highly selective for PPARdelta and were dependent on the point of attachment of the substituent. In the 1,4-series, analog 28e was found to be the most potent (IC(50)=1.7 nM) and selective (>1000-fold) compound for PPARdelta. None of the compounds tested showed appreciable binding affinity for PPARgamma.
Subject(s)
Carboxylic Acids/chemistry , Chemistry, Pharmaceutical/methods , PPAR delta/agonists , Drug Design , Humans , Inhibitory Concentration 50 , Ligands , Lipids/chemistry , Models, Chemical , PPAR delta/chemistry , Protein Binding , Structure-Activity Relationship , Sulfhydryl Compounds/chemistry , TemperatureABSTRACT
In an effort to identify hepatoselective inhibitors of HMG-CoA reductase, two series of pyrroles were synthesized and evaluated. Efforts were made to modify (3R,5R)-7-[3-(4-fluorophenyl)-1-isopropyl-4-phenyl-5-phenylcarbamoyl-1H-pyrrol-2-yl]-3,5-dihydroxy-heptanoic acid sodium salt 30 in order to reduce its lipophilicity and therefore increase hepatoselectivity. Two strategies that were explored were replacement of the lipophilic 3-phenyl substituent with either a polar function (pyridyl series) or with lower alkyl substituents (lower alkyl series) and attachment of additional polar moieties at the 2-position of the pyrrole ring. One compound was identified to be both highly hepatoselective and active in vivo. We report the discovery, synthesis, and optimization of substituted pyrrole-based hepatoselective ligands as potent inhibitors of HMG-CoA reductase for reducing low density lipoprotein cholesterol (LDL-c) in the treatment of hypercholesterolemia.
Subject(s)
Hydroxymethylglutaryl CoA Reductases/metabolism , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemical synthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Liver/drug effects , Liver/enzymology , Pyrroles/chemistry , Pyrroles/pharmacology , Animals , Cholesterol/biosynthesis , Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemistry , Ligands , Male , Microsomes, Liver/drug effects , Microsomes, Liver/enzymology , Molecular Structure , Pyrroles/chemical synthesis , Rats , Rats, Sprague-DawleyABSTRACT
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.
Subject(s)
Hydroxymethylglutaryl-CoA Reductase Inhibitors/chemistry , Hydroxymethylglutaryl-CoA Reductase Inhibitors/pharmacology , Pyrroles/chemistry , Pyrroles/pharmacology , Animals , Cricetinae , Dose-Response Relationship, Drug , Drug Design , Fluorobenzenes , Hyperlipidemias/drug therapy , Liver/drug effects , Models, Molecular , Molecular Structure , Pyrimidines , Rosuvastatin Calcium , Structure-Activity Relationship , SulfonamidesABSTRACT
Interleukin-8 modulation is implicated in many inflammatory and cancer diseases. Starting from a mass-screening hit, the synthesis and structure-activity relationship of 2-amino-3-heteroarylquinoxalines as non-peptide, small molecule interleukine-8 receptor antagonists have been developed. The optimized derivatives, PD 0210293 (13y) and PD 0220245 (13r), show inhibition of both IL-8 receptor binding and IL-8-mediated neutrophil chemotaxis.