ABSTRACT
G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) is a free fatty acid (FFA) receptor that mediates FFA-amplified glucose-stimulated insulin secretion in pancreatic ß-cells. We previously identified (2,3-dihydro-1-benzofuran-3-yl)acetic acid derivative 2 as a candidate, but it had relatively high lipophilicity. Adding a polar functional group on 2 yielded several compounds with lower lipophilicity and little effect on caspase-3/7 activity at 30 µM (a marker of toxicity in human HepG2 hepatocytes). Three optimized compounds showed promising pharmacokinetic profiles with good in vivo effects. Of these, compound 16 had the lowest lipophilicity. Metabolic analysis of 16 showed a long-acting PK profile due to high resistance to ß-oxidation. Oral administration of 16 significantly reduced plasma glucose excursion and increased insulin secretion during an OGTT in type 2 diabetic rats. Compound 16 (TAK-875) is being evaluated in human clinical trials for the treatment of type 2 diabetes.
Subject(s)
Benzofurans/pharmacology , Glucose/pharmacology , Insulin/metabolism , Receptors, G-Protein-Coupled/agonists , Sulfones/pharmacology , Animals , Benzofurans/chemical synthesis , Benzofurans/pharmacokinetics , Diabetes Mellitus, Type 2/drug therapy , Female , Glucose Tolerance Test , Hep G2 Cells , Humans , Insulin Secretion , Male , Rats , Receptors, G-Protein-Coupled/drug effects , Stereoisomerism , Sulfones/chemical synthesis , Sulfones/pharmacokineticsABSTRACT
In our search for a novel class of non-TZD, non-carboxylic acid peroxisome proliferator-activated receptor (PPAR) γ agonists, we explored alternative lipophilic templates to replace benzylpyrazole core of the previously reported agonist 1. Introduction of a pentylsulfonamide group into arylpropionic acids derived from previous in-house PPARγ ligands succeeded in the identification of 2-pyridyloxybenzene-acylsulfonamide 2 as a lead compound. Docking studies of compound 2 suggested that a substituent para to the central benzene ring should be incorporated to effectively fill the Y-shaped cavity of the PPARγ ligand-binding domain (LBD). This strategy led to significant improvement of PPARγ activity. Further optimization to balance in vitro activity and metabolic stability allowed the discovery of the potent, selective and orally efficacious PPARγ agonist 8f. Structure-activity relationship study as well as detailed analysis of the binding mode of 8f to the PPARγ-LBD revealed the essential structural features of this series of ligands.
Subject(s)
Drug Design , Peroxisome Proliferator-Activated Receptors/agonists , Pyridines/chemistry , Sulfonamides/chemistry , Sulfonamides/pharmacology , Acylation , Animals , Binding Sites , Blood Glucose/drug effects , CHO Cells , COS Cells , Chlorocebus aethiops , Cricetinae , Crystallography, X-Ray , Humans , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Male , Models, Molecular , Protein Binding/drug effects , Pyridines/administration & dosage , Pyridines/pharmacokinetics , Pyridines/pharmacology , Rats, Wistar , Structure-Activity RelationshipABSTRACT
As part of a program to identify potent GPR40 agonists with drug-like properties suitable for clinical development, the incorporation of polar substituents was explored with the intention of decreasing the lipophilicity of our recently disclosed phenylpropanoic acid derivative 1. This incorporation would allow us to mitigate the cytotoxicity issues observed with compound 1 and enable us to move away from the multifunctional free fatty acid-like structure. Substitutions on the 2',6'-dimethylbiphenyl ring were initially undertaken, which revealed the feasibility of introducing polar functionalities at the biphenyl 4'-position. Further optimization of this position and the linker led to the discovery of several 4'-alkoxybiphenyl derivatives, which showed potent GPR40 agonist activities with the best balance in terms of improved cytotoxicity profiles and favorable pharmacokinetic properties. Among them, 3-{2-fluoro-4-[({4'-[(4-hydroxy-1,1-dioxidotetrahydro-2H-thiopyran-4-yl)methoxy]-2',6'-dimethylbiphenyl-3-yl}methyl)amino]phenyl}propanoic acid (35) exhibited a robust plasma glucose-lowering effect and insulinotropic action during an oral glucose tolerance test in rats with impaired glucose tolerance.
Subject(s)
Cyclic S-Oxides/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Phenylpropionates/chemical synthesis , Receptors, G-Protein-Coupled/agonists , Animals , CHO Cells , Calcium/metabolism , Caspases/metabolism , Cell Survival , Cricetinae , Cyclic S-Oxides/pharmacokinetics , Cyclic S-Oxides/therapeutic use , Diabetes Mellitus, Type 2/drug therapy , Female , Glucose Intolerance/drug therapy , Hep G2 Cells , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , Inhibitory Concentration 50 , Male , Phenylpropionates/pharmacokinetics , Phenylpropionates/therapeutic use , Rats , Receptors, G-Protein-Coupled/metabolism , Structure-Activity RelationshipABSTRACT
Herein, we describe the design, synthesis, and structure-activity relationships of novel benzylpyrazole acylsulfonamides as non-thiazolidinedione (TZD), non-carboxylic-acid-based peroxisome proliferator-activated receptor (PPAR) γ agonists. Docking model analysis of in-house weak agonist 2 bound to the reported PPARγ ligand binding domain suggested that modification of the carboxylic acid of 2 would help strengthen the interaction of 2 with the TZD pocket and afford non-carboxylic-acid-based agonists. In this study, we used an acylsulfonamide group as the ring-opening analog of TZD as an isosteric replacement of carboxylic acid moiety of 2; further, preliminary modification of the terminal alkyl chain on the sulfonyl group gave the lead compound 3c. Subsequent optimization of the resulting compound gave the potent agonists 25c, 30b, and 30c with high metabolic stability and significant antidiabetic activity. Further, we have described the difference in binding mode of the carboxylic-acid-based agonist 1 and acylsulfonamide 3d.
Subject(s)
Drug Design , Hypoglycemic Agents/chemical synthesis , PPAR gamma/agonists , Pyrazoles/chemistry , Sulfonamides/chemistry , Animals , Binding Sites , Carboxylic Acids/chemistry , Computer Simulation , Diabetes Mellitus, Experimental/drug therapy , Disease Models, Animal , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/therapeutic use , PPAR gamma/metabolism , Protein Structure, Tertiary , Rats , Sulfonamides/pharmacokinetics , Sulfonamides/therapeutic use , Thiazolidinediones/chemistryABSTRACT
The G protein-coupled receptor 40 (GPR40)/free fatty acid receptor 1 (FFA1) has emerged as an attractive target for a novel insulin secretagogue with glucose dependency. We previously identified phenylpropanoic acid derivative 1 (3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid) as a potent and orally available GPR40/FFA1 agonist; however, 1 exhibited high clearance and low oral bioavailability, which was likely due to its susceptibility to ß-oxidation at the phenylpropanoic acid moiety. To identify long-acting compounds, we attempted to block the metabolically labile sites at the phenylpropanoic acid moiety by introducing a fused-ring structure. Various fused-ring alkanoic acids with potent GPR40/FFA1 activities and good PK profiles were produced. Further optimizations of the lipophilic portion and the acidic moiety led to the discovery of dihydrobenzofuran derivative 53 ((6-{[4'-(2-ethoxyethoxy)-2',6'-dimethylbiphenyl-3-yl]methoxy}-2,3-dihydro-1-benzofuran-3-yl)acetic acid), which acted as a GPR40/FFA1 agonist with in vivo efficacy during an oral glucose tolerance test (OGTT) in rats with impaired glucose tolerance.
Subject(s)
Acetates/chemical synthesis , Acids, Acyclic/chemical synthesis , Benzofurans/chemical synthesis , Insulin/blood , Receptors, G-Protein-Coupled/agonists , Acetates/pharmacokinetics , Acetates/pharmacology , Acids, Acyclic/pharmacokinetics , Acids, Acyclic/pharmacology , Animals , Benzofurans/pharmacokinetics , Benzofurans/pharmacology , CHO Cells , Cricetinae , Cricetulus , Female , Glucose Intolerance/metabolism , Glucose Tolerance Test , Humans , Insulin/metabolism , Insulin Secretion , Models, Molecular , Protein Binding , Rats , Rats, Wistar , Species SpecificityABSTRACT
G protein-coupled receptor 40/free fatty acid receptor 1 (GPR40/FFA(1)) is highly expressed in pancreatic ß cells and mediates free fatty acid-induced insulin secretion. This study examined the pharmacological effects and potential for avoidance of lipotoxicity of [(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}meth-oxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate) (TAK-875), a novel, orally available, selective GPR40 agonist. Insulinoma cell lines and primary rat islets were used to assess the effects of TAK-875 in vitro. The in vivo effects of TAK-875 on postprandial hyperglycemia, fasting hyperglycemia, and normoglycemia were examined in type 2 diabetic and normal rats. In rat insulinoma INS-1 833/15 cells, TAK-875 increased intracellular inositol monophosphate and calcium concentration, consistent with activation of the Gqα signaling pathway. The insulinotropic action of TAK-875 (10 µM) in INS-1 833/15 and primary rat islets was glucose-dependent. Prolonged exposure of cytokine-sensitive INS-1 832/13 to TAK-875 for 72 h at pharmacologically active concentrations did not alter glucose-stimulated insulin secretion, insulin content, or caspase 3/7 activity, whereas prolonged exposure to palmitic or oleic acid impaired ß cell function and survival. In an oral glucose tolerance test in type 2 diabetic N-STZ-1.5 rats, TAK-875 (1-10 mg/kg p.o.) showed a clear improvement in glucose tolerance and augmented insulin secretion. In addition, TAK-875 (10 mg/kg, p.o.) significantly augmented plasma insulin levels and reduced fasting hyperglycemia in male Zucker diabetic fatty rats, whereas in fasted normal Sprague-Dawley rats, TAK-875 neither enhanced insulin secretion nor caused hypoglycemia even at 30 mg/kg. TAK-875 enhances glucose-dependent insulin secretion and improves both postprandial and fasting hyperglycemia with a low risk of hypoglycemia and no evidence of ß cell toxicity.
Subject(s)
Benzofurans/pharmacology , Diabetes Mellitus, Type 2/drug therapy , Glucose/physiology , Hyperglycemia/drug therapy , Hypoglycemic Agents , Insulin/metabolism , Receptors, G-Protein-Coupled/agonists , Sulfones/pharmacology , Animals , Blood Glucose/metabolism , CHO Cells , Calcium/metabolism , Caspase 3/metabolism , Caspase 7/metabolism , Cell Survival/drug effects , Cricetinae , Cricetulus , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/drug therapy , Diabetes Mellitus, Type 2/blood , Fasting/physiology , Hyperglycemia/blood , Insulin Resistance/physiology , Insulin-Secreting Cells/drug effects , Insulin-Secreting Cells/metabolism , Male , Postprandial Period/physiology , Rats , Rats, Sprague-Dawley , Signal Transduction/drug effectsABSTRACT
G protein-coupled receptor 40 (GPR40) is being recently considered to be a new potential drug target for the treatment of type 2 diabetes because of its role in the enhancement of free fatty acid-regulated glucose-stimulated insulin secretion in pancreatic ß-cells. We initially identified benzyloxyphenylpropanoic acid (1b) (EC(50) = 510 nM), which was designed based on the structure of free fatty acids, as a promising lead compound with GPR40 agonist activity. Chemical modification of compound 1b led to the discovery of 3-{4-[(2',6'-dimethylbiphenyl-3-yl)methoxy]-2-fluorophenyl}propanoic acid (4p) as a potent GPR40 agonist (EC(50) = 5.7 nM). Compound 4p exhibited acceptable pharmacokinetic profiles and significant glucose-lowering effects during an oral glucose tolerance test in diabetic rats. Moreover, no hypoglycemic event was observed even after administration of a high dose of compound 4p to normal fasted rats. These pharmacological results suggest that GPR40 agonists might be novel glucose-dependent insulin secretagogues with little or no risk of hypoglycemia.
Subject(s)
Biphenyl Compounds/chemical synthesis , Hypoglycemic Agents/chemical synthesis , Phenylpropionates/chemical synthesis , Receptors, G-Protein-Coupled/agonists , Administration, Oral , Animals , Biphenyl Compounds/pharmacokinetics , Biphenyl Compounds/pharmacology , Blood Glucose/analysis , CHO Cells , Cricetinae , Cricetulus , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/drug therapy , Drug Design , Glucose Tolerance Test , Humans , Hypoglycemic Agents/pharmacokinetics , Hypoglycemic Agents/pharmacology , Male , Phenylpropionates/pharmacokinetics , Phenylpropionates/pharmacology , Rats , Rats, Sprague-Dawley , Stereoisomerism , Structure-Activity RelationshipABSTRACT
GPR40, one of the G protein-coupled receptors predominantly expressed in pancreatic ß-cells, mediates enhancement of glucose-stimulated insulin secretion by free fatty acids. A potent and selective GPR40 agonist is theorized to be a safe and effective antidiabetic drug with little or no risk of hypoglycemia. Cyclization of the phenylpropanoic acid moiety of lead compound 1 produced fused phenylalkanoic acids with favorable in vitro agonist activities and pharmacokinetic profiles. Further optimization led to the discovery of dihydrobenzofuran derivative 9a ([(3S)-6-({2',6'-dimethyl-4'-[3-(methylsulfonyl)propoxy]biphenyl-3-yl}methoxy)-2,3-dihydro-1-benzofuran-3-yl]acetic acid hemi-hydrate, TAK-875) as a potent, selective, and orally bioavailable GPR40 agonist, with a pharmacokinetic profile enabling long-acting drug efficacy. Compound 9a showed potent plasma glucose-lowering action and insulinotropic action during an oral glucose tolerance test in female Wistar fatty rats with impaired glucose tolerance. Compound 9a is currently in clinical trials for the treatment of type 2 diabetes mellitus.
ABSTRACT
An epidemic of metabolic diseases including type 2 diabetes and obesity is undermining the health of people living in industrialized societies. There is an urgent need to develop innovative therapeutics. The peroxisome proliferator-activated receptor gamma (PPARgamma) is one of the ligand-activated transcription factors in the nuclear hormone receptor superfamily and a pivotal regulator of glucose and lipid homeostasis. The discovery of PPARgamma as a target of multimodal insulin sensitizers, represented by thiazolidinediones (TZDs), has attracted remarkable scientific interest and had a great impact on the pharmaceutical industry. With the clinical success of the PPARgamma agonists, pioglitazone (Actos) and rosiglitazone (Avandia), development of novel and potent insulin-sensitizing agents with diverse clinical profiles has been accelerated. Currently, a number of PPARgamma agonists from different chemical classes and with varying pharmacological profiles are being developed. Despite quite a few obstacles to the development of PPAR-related drugs, PPARgamma-targeted agents still hold promise. There are new concepts and encouraging evidence emerging that suggest this class can yield improved anti-diabetic agents. This review covers the discovery of TZDs, provides an overview of PPARgamma including the significance of PPARgamma as a drug target, describes the current status of a wide variety of novel PPARgamma ligands including PPAR dual and pan agonists and selective PPARgamma modulators (SPPARgammaMs), and highlights new approaches for identifying agents targeting PPARgamma in the treatment of type 2 diabetes.
Subject(s)
Hypoglycemic Agents/therapeutic use , Insulin/metabolism , PPAR gamma/agonists , Diabetes Mellitus, Type 2/drug therapy , Ligands , Pioglitazone , Rosiglitazone , Thiazolidinediones/therapeutic useABSTRACT
A novel oxyiminoalkanoic acid derivative, TAK-559, (E)-4-[4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino]-4-phenylbutyric acid, was synthesized as a candidate of a new type of insulin-sensitizing agent. We report here activation of human peroxisome proliferator-activated receptor (hPPAR) subtypes by TAK-559. In a transient transactivation assay, TAK-559 was a potent hPPARgamma1 and hPPARalpha agonist with EC50 values of 31 and 67 nM, respectively. Furthermore, TAK-559 was a partial agonist for hPPARgamma1 with about 68% of maximal activation obtained with rosiglitazone (5-(4-(2-(methyl(2-pyridinyl)amino)ethoxy) benzyl)-1,3-thiazolidine-2,4-dione), a thiazolidinedione derivative, which is known as a PPARgamma agonist. PPARdelta was significantly activated at a high concentration (10 microM) of TAK-559. Competition-binding assays using radiolabeled ligand indicated that the transactivation of all hPPAR subtypes by TAK-559 was due to direct binding of TAK-559 to each subtype. We also demonstrated that TAK-559 acts to recruit the coactivator SRC-1 to each of hPPARgamma1 and hPPARalpha, and to dissociate the corepressor NCoR from each of hPPARgamma1 and hPPARalpha. Taken together, we conclude that TAK-559 is a dual agonist for hPPARgamma1 and hPPARalpha with nearly equal EC50 values, a partial agonist for hPPARgamma1, and has a rather slight agonist activity for hPPARdelta.
Subject(s)
Butyrates/pharmacology , Oxazoles/pharmacology , PPAR gamma/drug effects , 3T3 Cells , Adipocytes/drug effects , Adipocytes/metabolism , Animals , Butyrates/metabolism , COS Cells , Chlorocebus aethiops , DNA-Binding Proteins/drug effects , DNA-Binding Proteins/genetics , DNA-Binding Proteins/metabolism , Dose-Response Relationship, Drug , Drug Evaluation, Preclinical/methods , Histone Acetyltransferases , Humans , Hypoglycemic Agents/metabolism , Hypoglycemic Agents/pharmacology , Japan , Mice , Nuclear Receptor Coactivator 1 , Oxazoles/metabolism , PPAR gamma/genetics , RNA, Messenger/drug effects , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rosiglitazone , Thiazolidinediones/pharmacology , Transcription Factor AP-2 , Transcription Factors/drug effects , Transcription Factors/genetics , Transcription Factors/metabolism , Transcription Factors/pharmacology , TransfectionABSTRACT
Preparation and biological activity of the metabolites of the potent antihyperglycemic and antihyperlipidemic agent, (E)-4-(4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino)-4-phenylbutyric acid (TAK-559) (1), were investigated. Metabolites M-I (2), M-II (3), M-III (4) and M-IV (5) were synthesized and their biological activities were evaluated by in vitro and in vivo experiments. Compounds 2-4 activate human peroxisome proliferator-activated receptor gamma one (hPPARgamma1) and hPPARalpha, but their activities are weaker than those of TAK-559 (1). Compound 5 only activates hPPARgamma1 weakly. TAK-559 (1) showed potent in vivo plasma glucose and triglyceride lowering activities in Wistar fatty rats after intraperitoneal administration, while its metabolites (2-5) showed comparatively weak activities.
Subject(s)
Butyrates/chemistry , Butyrates/pharmacology , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Oxazoles/chemistry , Oxazoles/pharmacology , Animals , Biotransformation , Blood Glucose/metabolism , Butyrates/metabolism , COS Cells , Chlorocebus aethiops , Chromatography, High Pressure Liquid , Dose-Response Relationship, Drug , Genes, Reporter/genetics , Humans , Hypoglycemic Agents/metabolism , Injections, Intraperitoneal , Magnetic Resonance Spectroscopy , Male , Mass Spectrometry , Oxazoles/metabolism , Rats , Rats, Wistar , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Receptors, Retinoic Acid/genetics , Retinoid X Receptors , Spectrophotometry, Infrared , Transcription Factors/antagonists & inhibitors , Transcription Factors/genetics , Transfection , Triglycerides/bloodABSTRACT
A novel series of 5-(omega-aryloxyalkyl)oxazole derivatives was prepared and their effects on brain-derived neurotrophic factor (BDNF) production were evaluated in human neuroblastoma (SK-N-SH) cells. Syntheses were performed by construction of an oxazole ring as a key reaction. Most of the 5-(omega-aryloxyalkyl)oxazole derivatives markedly increased BDNF production in SK-N-SH cells. 4-(4-Chlorophenyl)-2-(2-methyl-1H-imidazol-1-yl)-5-[3-(2-methoxyphenoxy)propyl]-1, 3-oxazole, one of the most promising compounds, showed potent activity (EC(50)=7.9 microM) and the improvement of the motor nerve conduction velocity and the tail-flick response accompanied by a recovery of the brain-derived neurotrophic factor level in the sciatic nerve of streptozotocin (STZ)-diabetic rats.
Subject(s)
Alkanes/chemical synthesis , Brain Chemistry/drug effects , Brain-Derived Neurotrophic Factor/biosynthesis , Oxazoles/chemical synthesis , Alkanes/pharmacology , Animals , Blood Glucose/metabolism , Body Weight/drug effects , Brain Neoplasms/metabolism , Cell Line, Tumor , Diabetes Mellitus, Experimental/complications , Diabetic Neuropathies/drug therapy , Humans , Indicators and Reagents , Magnetic Resonance Spectroscopy , Male , Neural Conduction/drug effects , Neuroblastoma/metabolism , Oxazoles/pharmacology , Rats , Rats, Sprague-Dawley , Reaction Time/drug effects , Stimulation, Chemical , Structure-Activity Relationship , Subcellular Fractions/chemistryABSTRACT
We previously reported that (Z)-2-(4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino)-2-(4-phenoxyphenyl)acetic acid (3) showed potent glucose and lipid lowering effects in genetically obese and diabetic mice, KKA(y). This compound also showed transcriptional activity for peroxisome proliferator-activated receptor (PPAR)-gamma. We expanded on the structure-activity relationships of oxyiminoalkanoic acid derivatives based on this transcriptional activity (in vitro). Insertion of a carbon chain between the imino carbon and the carboxyl moiety of (Z)-2-(4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino)-2-phenylacetic acid (2) resulted in a marked increase in transcriptional activity at PPARgamma. In vivo potencies of synthesized compounds, which showed strong functional activity at PPARgamma, were tested using KKA(y) mice. Among these compounds, (E)-4-(4-[(5-methyl-2-phenyl-1, 3-oxazol-4-yl)methoxy]benzyloxyimino)-4-phenylbutyric acid (27) exhibited marked glucose and lipid lowering activity while showing no significant body weight gain. Compound (27) (TAK-559) showed favorable pharmacokinetic properties with good absorption and duration, and was considered as an attractive candidate for further evaluation.
Subject(s)
Blood Glucose/drug effects , Hypoglycemic Agents/chemistry , Hypoglycemic Agents/pharmacology , Lipids/antagonists & inhibitors , Thiazolidinediones , Alkenes/chemistry , Alkenes/pharmacology , Animals , Blood Glucose/metabolism , Cricetinae , Humans , Imino Acids/chemistry , Imino Acids/pharmacology , Lipids/blood , Mice , Rats , Rats, Sprague-Dawley , Structure-Activity Relationship , Thiazoles/chemistry , Thiazoles/isolation & purificationABSTRACT
A novel series of oxyiminoacetic acid derivatives were synthesized in an effort to develop a potent antidiabetic agent, which does not contain the 2,4-thiazolidinedione moiety. These compounds were evaluated for glucose and lipid lowering effects in genetically obese and diabetic KKA(y) mice. Several of the compounds showed strong antidiabetic activity, including functional potency at peroxisome proliferator-activated receptor (PPAR)-gamma. (Z)-2-[4-[(5-Methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyloxyimino]-2-(4-phenoxyphenyl)acetic acid (25) significantly reduced plasma glucose (33%, p<0.01) and plasma triglycelide levels (43%, p<0.01) even at a dosage of 0.001% in diet. Pharmacokinetic analyses of 25 are also reported.
Subject(s)
Acetic Acid/chemistry , Hypoglycemic Agents/chemistry , Imino Acids/chemistry , Thiazolidinediones , Acetic Acid/pharmacology , Acetic Acid/therapeutic use , Animals , Diabetes Mellitus, Experimental/blood , Diabetes Mellitus, Experimental/drug therapy , Female , Humans , Hypoglycemic Agents/pharmacology , Hypoglycemic Agents/therapeutic use , Imino Acids/pharmacology , Imino Acids/therapeutic use , Male , Mice , Mice, Obese , Rats , Rats, Sprague-Dawley , Thiazoles/chemistry , Thiazoles/therapeutic useABSTRACT
Two novel classes of 2,4-thiazolidinediones and 2,4-oxazolidinediones with an omega-(azolylalkoxyphenyl)alkyl substituent at the 5-position were prepared and their antidiabetic effects were evaluated in two genetically obese and diabetic animal models, KKA(y) mice and Wistar fatty rats. A large number of the 2,4-thia(oxa)zolidinediones showed potent glucose- and lipid-lowering activities. The antidiabetic activities of the 2,4-oxazolidinediones were superior to those of the 2,4-thiazolidinediones. Among the compounds, both enantiomers of 5-[3-[4-[2-(2-furyl)-5-methyl-4-oxazolylmethoxy]-3-methoxyphenyl]propyl]-2,4-oxazolidinedione (64), one of the most interesting compounds in terms of activity, were synthesized by using an asymmetric O-acetylation of the corresponding alpha-hydroxyvalerate (26) with immobilized lipase, followed by cyclization of the oxazolidinedione ring. (R)-(+)-64 showed more potent glucose-lowering activity (effective dose (ED)25 = 0.561 mg/kg/d) than (S)-(-)-64 (ED25 > 1.5 mg/kg/d) or pioglitazone (ED25 = 6 mg/kg/d) in KKA(y) mice. It also exhibited a 10-fold more potent antidiabetic activity (ED25 = 0.05 mg/kg/d) than pioglitazone (ED25 = 0.5 mg/kg/d) in Wistar fatty rats. The antidiabetic effects of this compound are considered to be due to its potent agonistic activity for peroxisome proliferator-activated receptor gamma (EC(50) = 8.87 nM).
Subject(s)
Hypoglycemic Agents/chemical synthesis , Hypoglycemic Agents/pharmacology , Oxazolidinones/chemistry , Oxazolidinones/pharmacology , Thiazoles/chemistry , Thiazoles/pharmacology , Thiazolidinediones , Animals , COS Cells , Chromatography, High Pressure Liquid , Crystallography, X-Ray , Diabetes Mellitus/drug therapy , Insulin/blood , Male , Mice , Models, Chemical , Models, Molecular , Rats , Rats, Wistar , TemperatureABSTRACT
A series of 5-(4-alkoxyphenylalkyl)-1H-tetrazole derivatives, containing an oxazole-based group at the alkoxy moiety, was prepared and their antidiabetic effects were evaluated in two genetically obese and diabetic animal models, KKAy mice and Wistar fatty rats. Syntheses were performed by cyclization of the corresponding nitrites reacting with azide compounds. A large number of the 5-(4-alkoxyphenylalkyl)-1H-tetrazoles showed potent glucose and lipid lowering activities in KKAy mice. In particular, 5-[3-[6-(5-methyl-2-phenyl-4-oxazolyl-methoxy)-3-pyridyl]propyl]-1H-tetrazole had potent glucose lowering activity (ED25=0.0839 mg x kg(-1) x d(-1)), being 72 times more active than pioglitazone hydrochloride (ED25=6.0 mg x kg(-1) x d(-1)). This compound also showed strong glucose lowering (ED25=0.0873 mg x kg(-1) x d(-1)) and lipid lowering effects (ED25=0.0277 mg x kg(-1) x d(-1)) in Wistar fatty rats. The antidiabetic effects of this compound are considered to be due to its potent agonistic activity for peroxisome proliferator-activated receptor gamma (PPARgamma) (EC50 = 6.75 nM).