ABSTRACT
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
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
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
Recent literature has suggested the benefit of selective PPARdelta agonists for the treatment of atherosclerosis and other disease states associated with the metabolic syndrome. Herein we report the synthesis and structure-activity relationships of a series of novel and selective PPARdelta agonists. Our search began with identification of a novel benzothiophene template which was modified by the addition of various thiazolyl, isoxazolyl, and benzyloxy-benzyl moieties. Further elucidation of the SAR led to the identification of benzofuran and indole based templates. During the course of our research, we discovered three new chemical templates with varying degrees of affinity and potency for PPARdelta versus the PPARalpha and PPARgamma subtypes.
