ABSTRACT
2,3-Dihydro-3,8-diphenylbenzo[1,4]oxazines were identified as a new class of potent cholesteryl ester transfer protein inhibitors. The most potent compound 6a (IC50=26 nM) possessed a favorable pharmacokinetic profile with good oral bioavailability in rat (F=53%) and long human liver microsome stability (t(1/2)=62 min). It increased HDL-C in human CETP transgenic mice and high-fat fed hamsters. The structure and activity relationship of this series will be described in this Letter.
Subject(s)
Benzoxazines/chemical synthesis , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Drug Design , Administration, Oral , Animals , Benzoxazines/chemistry , Benzoxazines/pharmacology , Cholesterol Ester Transfer Proteins/genetics , Cricetinae , Enzyme Inhibitors/chemical synthesis , Enzyme Inhibitors/chemistry , Enzyme Inhibitors/pharmacology , Female , Humans , Inhibitory Concentration 50 , Male , Mice , Mice, Transgenic , Molecular Structure , RatsABSTRACT
Tetrahydroquinoline A is a potent inhibitor of the cholesterol ester transfer protein (CETP), a target for the treatment of low HDL-C and atherosclerosis. Low HDL-C has been identified as a key risk factor for cardiovascular disease in addition to high LDL-C, the target of the statin drugs. Tetrahydroquinoline A inhibits partially purified CETP with an IC(50) of 39nM. The preparation of a series of potent inhibitors of CETP designed around a 1,2,3,4-tetrahydroquinoline platform will be discussed.
Subject(s)
Chemistry, Pharmaceutical/methods , Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Cholesterol Ester Transfer Proteins/chemistry , Quinolines/chemical synthesis , Quinolines/pharmacology , Animals , Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Cardiovascular Diseases/prevention & control , Cholesterol, HDL/metabolism , Dogs , Drug Design , Haplorhini , Humans , Inhibitory Concentration 50 , Mice , Models, Chemical , Risk FactorsABSTRACT
With the goal of identifying a CETP inhibitor with high in vitro potency and optimal in vivo efficacy, a conformationally constrained molecule was designed based on the highly potent and flexible 13. The synthetic chemistry efforts led to the discovery of the potent and selective 12. In high-fat fed hamsters, human CETP transgenic mice, and cynomolgus monkeys, the in vivo efficacy of 12 for raising HDL-C was demonstrated to be comparable to torcetrapib.
Subject(s)
Cholesterol Ester Transfer Proteins/antagonists & inhibitors , Quinolines/chemistry , Quinolines/pharmacology , Administration, Oral , Animals , Cricetinae , Dietary Fats/administration & dosage , Drug Design , Humans , Macaca fascicularis , Magnetic Resonance Spectroscopy , Mice , Quinolines/chemical synthesis , Spectrometry, Mass, Electrospray IonizationABSTRACT
Synthesis and SAR of para-alkylthiophenoxyacetic acids is described. Achiral compounds 30, 31 and 32 were identified as potent and selective PPARdelta agonists.
Subject(s)
Glycolates/chemical synthesis , Glycolates/pharmacology , PPAR delta/agonists , Combinatorial Chemistry Techniques , Drug Design , Drug Discovery , Drug Evaluation, Preclinical , Glycolates/chemistry , Humans , Models, Molecular , Molecular Structure , Stereoisomerism , Structure-Activity Relationship , Thiazoles/pharmacologyABSTRACT
Peroxisome proliferator-activated receptor alpha (PPARalpha) is a member of the nuclear receptor family of ligand-activated transcription factors. It plays an important role in the regulation of genes involved in lipid metabolism and transport. Compound A is a potent and orally active PPARalpha agonist that activated both human and rat PPARalpha receptors. The compound induced the expression of genes involved in fatty acid metabolism in a rodent hepatoma cell line and in the liver of db/db mouse. The ability of compound A to stimulate fatty acid beta-oxidation was demonstrated in human hepatocytes and human skeletal muscle cells, which confirmed a functional activation of PPARalpha-mediated activities. Compound A was shown to be a more potent and efficacious antidyslipidemic agent in atherogenic rat and db/db mouse models as compared with fenofibrate. The increase in high-density lipoprotein cholesterol levels by compound A was at least partially due to an increase in serum apolipoprotein A-I protein concentrations in human PPARalpha transgenic mouse. The triglyceride-lowering effect was further confirmed in a higher species, obese dog models. In addition, compound A dose-dependently ameliorated hyperglycemia and hyperinsulinemia, and improved glucose tolerance in db/db mice. In a diet-induced obesity mouse model, compound A decreased body weight mainly by increasing energy expenditure and reducing fat deposition. In conclusion, the novel and potent PPARalpha agonist improves lipid profile, insulin sensitivity, and energy balance in animal models.
Subject(s)
Dyslipidemias/drug therapy , Energy Metabolism/drug effects , Indans/pharmacology , Insulin Resistance , PPAR alpha/agonists , Phenylurea Compounds/pharmacology , Animals , Apolipoprotein A-I/blood , Dogs , Dose-Response Relationship, Drug , Fatty Acids/metabolism , Female , Gene Expression Regulation/drug effects , Humans , Hyperinsulinism/drug therapy , Indans/therapeutic use , Lipids/blood , Male , Mice , Mice, Inbred C57BL , Mice, Obese , Oxidation-Reduction , Phenylurea Compounds/therapeutic use , Rats , Rats, Sprague-DawleyABSTRACT
Replacement of the methyl-thiazole moiety of GW501516 (a PPARdelta selective agonist) with [1,2,4]thiadiazole gave compound 21 which unexpectedly displayed submicromolar potency as a partial agonist at PPARalpha in addition to the high potency at PPARdelta. A structure-activity relationships study of 21 resulted in the identification of 40 as a potent and selective PPARalpha/delta dual agonist. Compound 40 and its close analogs represent a new series of PPARalpha/delta dual agonists. The high potency, high selectivity, significant gene induction, excellent PK profiles, low P450 inhibition or induction, and good in vivo efficacy in four animal models support 40 being selected as a pre-clinical study candidate, and may render 40 as a valuable pharmacological tool in elucidating the complex roles of PPARalpha/delta dual agonists, and the potential usage for the treatment of metabolic syndrome.
Subject(s)
PPAR alpha/agonists , PPAR delta/agonists , Thiadiazoles/chemistry , Thiadiazoles/pharmacology , Administration, Oral , Animals , Biological Availability , Gene Expression Regulation/drug effects , Metabolic Syndrome/drug therapy , Mice , Thiadiazoles/chemical synthesis , Thiadiazoles/pharmacokinetics , Transcriptional ActivationABSTRACT
Cardiovascular disease is the most common cause of morbidity and mortality in developed nations. To effectively target dyslipidemia to reduce the risk of cardiovascular disease, it may be beneficial to activate the peroxisome proliferator-activated receptors (PPARs) PPARalpha and PPARdelta simultaneously through a single molecule. Replacement of the methylthiazole of 5 (the PPARdelta selective agonist) with [1,2,4]thiadiazole gave compound 13, which unexpectedly displayed submicromolar potency as a partial agonist at PPARalpha in addition to the high potency at PPARdelta. Optimization of 13 led to the identification of 24 as a potent and selective PPARalpha/delta dual agonist. Compound 24 and its close analogs represent a new series of PPARalpha/delta dual agonists. The high potency, significant gene induction, excellent PK profiles, and good in vivo efficacies in three animal models may render compound 24 as a valuable pharmacological tool in elucidating the complex roles of PPARalpha/delta dual agonists and as a potential treatment of the metabolic syndrome.
Subject(s)
Hypolipidemic Agents/chemical synthesis , PPAR alpha/agonists , PPAR delta/agonists , Thiadiazoles/chemical synthesis , Administration, Oral , Animals , Apolipoprotein A-I/genetics , Cell Line , Female , Humans , Hypolipidemic Agents/pharmacokinetics , Hypolipidemic Agents/pharmacology , Insulin Resistance , Male , Mice , Mice, Obese , Mice, Transgenic , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiadiazoles/pharmacokinetics , Thiadiazoles/pharmacologyABSTRACT
A novel series of potent and selective PPARdelta agonists, para-alkylthiophenoxyacetic acids, was identified. The synthesis and structure-activity relationships are described.
Subject(s)
Glycolates/pharmacology , PPAR delta/agonists , Area Under Curve , Glycolates/chemistry , Glycolates/pharmacokinetics , Structure-Activity RelationshipABSTRACT
A number of RXR modulators with novel structural features were synthesized and screened in the functional assays. The synthesis and the structure-activity relationship within the series of compounds will be presented. Some in vivo data generated in the models for dyslipidemia and diabetes will also be presented.
Subject(s)
Diabetes Mellitus/drug therapy , Dyslipidemias/drug therapy , Hypoglycemic Agents/pharmacology , Quinolones/pharmacology , Retinoid X Receptors/agonists , Animals , Disease Models, Animal , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/therapeutic use , Quinolones/chemical synthesis , Rats , Rats, Sprague-Dawley , Structure-Activity RelationshipABSTRACT
A number of RXR agonists were synthesized and screened in functional assays. The synthesis and the structure-activity relationship (SAR) within the series of compounds will be presented. Some in vivo data in rodent models for dyslipidemia and diabetes will also be presented.
Subject(s)
DNA-Binding Proteins/agonists , Diabetes Mellitus/drug therapy , Dyslipidemias/drug therapy , Hypoglycemic Agents/pharmacology , Receptors, Cytoplasmic and Nuclear/agonists , Retinoid X Receptors/agonists , Animals , DNA-Binding Proteins/metabolism , Dimerization , Disease Models, Animal , Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/therapeutic use , Liver X Receptors , Orphan Nuclear Receptors , Rats , Rats, Sprague-Dawley , Receptors, Cytoplasmic and Nuclear/metabolism , Retinoid X Receptors/metabolism , Structure-Activity RelationshipABSTRACT
GlaxoSmithKline and Ligand are developing GW-501516, a peroxisome proliferator-activator receptor-delta agonist for the potential treatment of dyslipidemia. Phase II clinical trials of this compound are ongoing.
Subject(s)
Hypolipidemic Agents/pharmacology , Thiazoles/pharmacology , Animals , Fatty Acids/metabolism , Glucose/metabolism , Humans , Macaca mulatta , Mice , Mice, Obese , PPAR delta/drug effects , PPAR delta/physiology , Structure-Activity Relationship , Thiazoles/chemical synthesis , Thiazoles/therapeutic useABSTRACT
This review describes the role of nuclear receptors in the regulation of genes involved in cholesterol transport and synthetic modulators of these receptors. Increasing the efflux of cholesterol from peripheral cells, such as lipid-laden macrophages, through a process called reverse cholesterol transport (RCT) requires HDL. Increasing the circulating levels of HDL, as well as the efficiency of the RCT process, could result in a reduction in the development of coronary artery disease and atherosclerosis. Nuclear receptors of the RXR heterodimer family have recently been shown to regulate key genes involved in HDL metabolism and reverse cholesterol transport. These include the PPARs (peroxisome proliferator activated receptors), the LXR (liver X receptor) and the farnesoid X receptor (FXR). The synthesis of specific and potent ligands for these receptors has aided in ascertaining the physiological role of these receptors as lipid sensors and the potential therapeutic utility of modulators of these receptors in dyslipidemias and cardiovascular disease.