oxadiazoles and Obesity

Diabetes mellitus type 2 (T2D) is a group of genetically heterogeneous metabolic disorders whose frequency has gradually risen worldwide. Diabetes mellitus Type 2 (T2D) has started to achieve a pandemic level, and it is estimated that within the next decade, cases of diabetes might get double due to increase in aging population. Diabetes is rightly called the 'silent killer' because it has emerged to be one of the major causes, leading to renal failure, loss of vision; besides cardiac arrest in India. Thus, a clinical requirement for the oral drug molecules monitoring glucose homeostasis appears to be unmet. GPR119 agonist, a family of G-protein coupled receptors, usually noticed in β-cells of pancreatic as well as intestinal L cells, drew considerable interest for type 2 diabetes mellitus (T2D). GPR119 monitors physiological mechanisms that enhance homeostasis of glucose, such as glucose-like peptide-1, gastrointestinal incretin hormone levels, pancreatic beta cell-dependent insulin secretion and glucose-dependent insulinotropic peptide (GIP). In this manuscript, we have reviewed the work done in the last five years (2015-2020) which gives an approach to design, synthesize, evaluate and study the structural activity relationship of novel GPR119 agonist-based lead compounds. Our article would help the researchers and guide their endeavours in the direction of strategy and development of innovative, effective GPR119 agonist-based compounds for the management of diabetes mellitus type 2.

Topics: Diabetes Mellitus, Type 2; Drug Design; Humans; Hypoglycemic Agents; Insulin-Secreting Cells; Obesity; Oxadiazoles; Receptors, G-Protein-Coupled; Structure-Activity Relationship

Arterial hypertension (AH) is one of the most common cardiovascular disease. Angiotensin II (AT II), the hormone of renin-angiotensin-aldosterone system, realizes its negative effects through AT 1 receptors - application point of angiotensin receptor blockers (ARB). Due to different dissociation AT 1 receptors properties some ARBs are more effective than others. Multiply multicenter randomized and observational studies approve the effectiveness and safety of azilsartan medoxomil in patients with AH 1-2 grade. Several preclinical studies have shown the additional properties of azilsartan, including increase of insulin sensitivity, cardio- and nephron protection in obesity. In our clinical case we showed the positive influence of azilsartan medoxomil on clinic and ambulatory blood pressure, 24-hour aortic stiffness parameters, longitudinal left ventricular strain in patient with AH and obesity.

Topics: Adult; Angiotensin II Type 1 Receptor Blockers; Antihypertensive Agents; Benzimidazoles; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Humans; Hypertension; Male; Obesity; Oxadiazoles

Topics: Albuminuria; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Animals; Antihypertensive Agents; Benzimidazoles; Blood Pressure; Diabetes Mellitus, Type 2; Disease Models, Animal; Humans; Hypertension; Insulin Resistance; Obesity; Oxadiazoles

Control of arterial hypertension in obese or overweight patients is complicated since obesity directly contributes to increased blood pressure, requiring new, highly effective antihypertensive drugs. This study evaluates the efficacy of azilsartan medoxomil in real clinical practice.. An international multicenter observational non-interventional prospective study of azilsartan medoxomil was conducted in 64 clinical centers in the Russian Federation and 5 centers in the Republic of Kazakhstan. This study included 1945 obese or overweight patients with arterial hypertension. Azilsartan medoxomil was prescribed in accordance with the approved instruction for use. The decision to prescribe the drug, dose adjustment and monitoring target BP achievement belonged to the attending physicians according to their routine clinical practice. The observation period took about 6 months.. The average duration of taking the medicine was 26.1 ± 4 weeks. By the fourth visit, the use of azilsartan medoxomil either in a monotherapy regimen or in free combinations resulted in a pronounced decrease in systolic and diastolic blood pressure by 30.5 ± 13.4 and 14 ± 9.4 mmHg, respectively (. Over the study time of 1945 patients, significant changes in blood pressure levels over time were noted, and a high frequency of response to the azilsartan therapy was observed. Adverse events related to the study drug were of mild or moderate intensity and did not require discontinuation of therapy. Thus, azilsartan medoxomil demonstrated a good safety profile and provided effective blood pressure control for overweight or obese patients with hypertension in real clinical practice.

Topics: Antihypertensive Agents; Benzimidazoles; Blood Pressure; Humans; Hypertension; Internationality; Male; Middle Aged; Obesity; Oxadiazoles; Prospective Studies

Topics: Animals; Blood Glucose; Diabetes Mellitus; Diet, High-Fat; Disease Models, Animal; Gene Expression Regulation, Enzymologic; Gluconeogenesis; Hep G2 Cells; Hepatocytes; Humans; Hypoglycemic Agents; Lipid Metabolism; Male; Mice, Inbred C57BL; Nerve Tissue Proteins; Obesity; Oxadiazoles; Palmitic Acid; Rats; Signal Transduction

Obesity is a health problem affecting more than 40% of US adults and 13% of the global population. Anti-obesity treatments including diet, exercise, surgery and pharmacotherapies have so far failed to reverse obesity incidence. Herein, we target obesity with a pharmacotherapeutic approach that decreases caloric efficiency by mitochondrial uncoupling. We show that a recently identified mitochondrial uncoupler BAM15 is orally bioavailable, increases nutrient oxidation, and decreases body fat mass without altering food intake, lean body mass, body temperature, or biochemical and haematological markers of toxicity. BAM15 decreases hepatic fat, decreases inflammatory lipids, and has strong antioxidant effects. Hyperinsulinemic-euglycemic clamp studies show that BAM15 improves insulin sensitivity in multiple tissue types. Collectively, these data demonstrate that pharmacologic mitochondrial uncoupling with BAM15 has powerful anti-obesity and insulin sensitizing effects without compromising lean mass or affecting food intake.

Topics: Adipose Tissue; Administration, Oral; Animals; Blood Glucose; Body Temperature; Body Weight; Diamines; Diet, Western; Disease Models, Animal; Dose-Response Relationship, Drug; Glucose Clamp Technique; Humans; Insulin Resistance; Liver; Male; Membrane Potential, Mitochondrial; Mice; Mitochondria; Obesity; Oxadiazoles; Oxidative Stress; Pyrazines

In rare cases, monogenetic obesity is caused by nonsense mutations in genes regulating energy balance. A key factor herein is the leptin receptor. Here, we focus on leptin receptor nonsense variants causing obesity, namely the human W31X, murine Y333X and rat Y763X mutations, and explored their susceptibilities to aminoglycoside and PTC124 mediated translational read-through in vitro. In a luciferase based assay, all mutations - when analysed within the mouse receptor - were prone to aminoglycoside mediated nonsense suppression with the highest susceptibility for W31X, followed by Y763X and Y333X. For the latter, the corresponding rodent models appear valuable for in vivo experiments. When W31X was studied in the human receptor, its superior read-through susceptibility - initially observed in the mouse receptor - was eliminated, likely due to the different nucleotide context surrounding the mutation in the two orthologues. The impact of the surrounding context on the read-through opens the possibility to discover novel sequence elements influencing nonsense suppression. As an alternative to toxic aminoglycosides, PTC124 was indicated as a superior nonsense suppressor but inconsistent data concerning its read-through activity are reported. PTC124 failed to rescue W31X as well as different nonsense mutated luciferase reporters, thus, challenging its ability to induce translational read-through.

Topics: Aminoglycosides; Animals; Codon, Nonsense; Genes, Reporter; HEK293 Cells; Humans; Luciferases; Mice; Obesity; Oxadiazoles; Rats; Receptors, Leptin

In this study, we present the translational modeling used in the discovery of AZD1979, a melanin-concentrating hormone receptor 1 (MCHr1) antagonist aimed for treatment of obesity. The model quantitatively connects the relevant biomarkers and thereby closes the scaling path from rodent to man, as well as from dose to effect level. The complexity of individual modeling steps depends on the quality and quantity of data as well as the prior information; from semimechanistic body-composition models to standard linear regression. Key predictions are obtained by standard forward simulation (e.g., predicting effect from exposure), as well as non-parametric input estimation (e.g., predicting energy intake from longitudinal body-weight data), across species. The work illustrates how modeling integrates data from several species, fills critical gaps between biomarkers, and supports experimental design and human dose-prediction. We believe this approach can be of general interest for translation in the obesity field, and might inspire translational reasoning more broadly.

Topics: Animals; Anti-Obesity Agents; Azetidines; Biomarkers; Body Weight; Dose-Response Relationship, Drug; Drug Discovery; Energy Intake; Female; Humans; Male; Mice; Models, Biological; Obesity; Oxadiazoles; Rats; Receptors, Pituitary Hormone; Research Design; Translational Research, Biomedical

G protein-coupled receptor 119 (GPR119) is a G protein-coupled receptor expressed predominantly in pancreatic β-cells and gastrointestinal enteroendocrine cells. Metformin is a first-line treatment of type 2 diabetes, with minimal weight loss in humans. In this study, we investigated the effects of GSK2041706 [2-([(1S)-1-(1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl)ethyl]oxy)-5-[4-(methylsulfonyl)phenyl]pyrazine], a GPR119 agonist, and metformin as monotherapy or in combination on body weight in a diet-induced obese (DIO) mouse model. Relative to vehicle controls, 14-day treatment with GSK2041706 (30 mg/kg b.i.d.) or metformin at 30 and 100 mg/kg b.i.d. alone caused a 7.4%, 3.5%, and 4.4% (all P < 0.05) weight loss, respectively. The combination of GSK2041706 with metformin at 30 or 100 mg/kg resulted in a 9.5% and 16.7% weight loss, respectively. The combination of GSK2041706 and metformin at 100 mg/kg caused a significantly greater weight loss than the projected additive weight loss of 11.8%. This body weight effect was predominantly due to a loss of fat. Cumulative food intake was reduced by 17.1% with GSK2041706 alone and 6.6% and 8.7% with metformin at 30 and 100 mg/kg, respectively. The combination of GSK2041706 with metformin caused greater reductions in cumulative food intake (22.2% at 30 mg/kg and 37.5% at 100 mg/kg) and higher fed plasma glucagon-like peptide 1 and peptide tyrosine tyrosine levels and decreased plasma insulin and glucose-dependent insulinotropic polypeptide levels compared with their monotherapy groups. In addition, we characterized the effect of GSK2041706 and metformin as monotherapy or in combination on neuronal activation in the appetite regulating centers in fasted DIO mice. In conclusion, our data demonstrate the beneficial effects of combining a GPR119 agonist with metformin in the regulation of body weight in DIO mice.

Topics: Animals; Body Weight; Diet, High-Fat; Dose-Response Relationship, Drug; Drug Synergism; Eating; Gastric Inhibitory Polypeptide; Glucagon-Like Peptide 1; Hypoglycemic Agents; Insulin; Male; Metformin; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oxadiazoles; Proto-Oncogene Proteins c-fos; Pyrazines; Receptors, G-Protein-Coupled; Weight Loss

In type 2 diabetes mellitus (T2DM) patients, the gradual loss of pancreatic β-cell function is a characteristic feature of disease progression that is associated with sustained hyperglycemia. Recently, G protein-coupled receptor 119 (GPR119) has been identified as a promising anti-diabetic therapeutic target. It is predominantly expressed in pancreatic β-cells, directly promotes glucose stimulated insulin secretion and indirectly increases glucagon-like peptide 1 (GLP-1) levels reducing appetite and food intake. Activation of GPR119 leads to insulin release in β-cells by increasing intracellular cAMP. Here, we identified a novel structural class of small-molecule GPR119 agonists, HD0471042, consisting of substituted a 3-isopropyl-1,2,4-oxadiazol-piperidine derivative with promising potential for the treatment of T2DM. The GPR119 agonist, HD0471042 increased intracellular cAMP levels in stably human GPR119 expressing CHO cell lines and HIT-T15 cell lines, hamster β-cell line expressing endogenously GPR119. HD0471042, significantly elevated insulin release in INS-1 cells of rat pancreatic β-cell line. In in vivo experiments, a single dose of HD0471042 improved glucose tolerance. Insulin and GLP-1 level were increased in a dose-dependent manner. Treatment with HD0471042 for 6 weeks in diet induced obesity mice and for 4 weeks in ob/ob and db/db mice improved glycemic control and also reduced weight gain in a dose-dependent manner. These data demonstrate that the novel GPR119 agonist, HD0471042, not only effectively controlled glucose levels, but also had an anti-obesity effect, a feature observed with GLP-1. We therefore suggest that HD0471042 represents a new type of anti-diabetes agent with anti-obesity potential for the effective treatment of type 2 diabetes.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; CHO Cells; Cricetulus; Cyclic AMP; Diabetes Mellitus, Type 2; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Design; Glucagon-Like Peptide 1; Humans; Hypoglycemic Agents; Insulin; Insulin-Secreting Cells; Male; Mice, Inbred C57BL; Obesity; Oxadiazoles; Piperidines; Rats; Receptors, G-Protein-Coupled; Structure-Activity Relationship; Time Factors; Transfection; Weight Gain

Angiotensin II type 1 receptor blockers (ARBs) are widely used in treating hypertension. In the present study, we tested the hypothesis that a novel ARB, azilsartan medoxomil (AZL-M) will prevent renal and cardiovascular injury in the spontaneously hypertensive obese rat (SHROB), a model of cardiometabolic syndrome.. Male SHROB were treated with vehicle or AZL-M orally for 56 days. Vehicle treated normotensive Wistar-Kyoto (WKY) rats served as controls. The effects of AZL-M on kidney injury, vascular endothelial and heart functions, lipid profile, and glucose tolerance were assessed.. AZL-M demonstrated anti-hypertensive effects along with markedly improved vascular endothelial function in SHROB. In these rats, AZL-M demonstrates strong kidney protective effects with lower albuminuria and nephrinuria along with reduced tubular cast formation and glomerular injury. AZL-M treatment also improved left ventricular heart function, attenuated development of left ventricular hypertrophy, and reduced cardiac fibrosis in SHROB.. Overall, these findings demonstrate kidney and heart protective effects of AZL-M in SHROB, and these effects were associated with its ability to lower blood pressure and improve endothelial function.

Topics: Animals; Antihypertensive Agents; Benzimidazoles; Blood Glucose; Body Weight; Cholesterol; Disease Models, Animal; Heart; Hypertension; Hypertrophy, Left Ventricular; In Vitro Techniques; Insulin; Kidney; Male; Mesenteric Arteries; Myocardium; Obesity; Oxadiazoles; Protective Agents; Rats, Inbred WKY; Triglycerides; Vasodilation

Topics: Animals; Antihypertensive Agents; Benzimidazoles; Hypertension; Male; Obesity; Oxadiazoles; Protective Agents

DGAT-1 is an enzyme that catalyzes the final step in triglyceride synthesis. mRNA knockout experiments in rodent models suggest that inhibitors of this enzyme could be of value in the treatment of obesity and type II diabetes. The carboxylic acid-based DGAT-1 inhibitor 1 was advanced to clinical trials for the treatment of type 2 diabetes, despite of the low passive permeability of 1. Because of questions relating to the potential attenuation of distribution and efficacy of a poorly permeable agent, efforts were initiated to identify compounds with improved permeability. Replacement of the acid moiety in 1 with an oxadiazole led to the discovery of 52, which possesses substantially improved passive permeability. The resulting pharmacodynamic profile of this neutral DGAT-1 inhibitor was found to be similar to 1 at comparable plasma exposures.

Topics: Administration, Oral; Animals; Diacylglycerol O-Acyltransferase; Drug Evaluation, Preclinical; Enzyme Inhibitors; Half-Life; Humans; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oxadiazoles; Oxazepines; Protein Binding; Rats; Structure-Activity Relationship

Angiotensin II receptor blockers (ARBs) are used widely for the treatment of heart failure. However, their use in obese and insulin-resistant patients remains controversial. To clarify their potential efficacy in these conditions, we administered azilsartan medoxomil (azilsartan), a prodrug of an angiotensin II receptor blocker to mice fed a high-fat diet (HFD) with left ventricular (LV) pressure overload (aortic banding). LV fibrosis (hydroxyproline), cardiac plasminogen activator inhibitor-1 (PAI-1; a marker of profibrosis), and creatine kinase (a marker of myocardial viability and energetics) were assessed. LV wall thickness and cardiac function were assessed echocardiographically. Mice given a HFD were obese and insulin resistant. Their LV hypertrophy was accompanied by greater LV PAI-1 and reduced LV creatine kinase compared with normal diet controls. Drug treatment reduced LV wall thickness, hypertrophy, and PAI-1 and increased cardiac output after aortic banding compared with results in HFD vehicle controls. Thus, azilsartan exerted favorable biological effects on the hearts of obese insulin-resistant mice subjected to LV pressure overload consistent with its potential utility in patients with analogous conditions.

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Cardiac Output; Creatine Kinase; Diet, High-Fat; Echocardiography; Heart Ventricles; Hypertrophy, Left Ventricular; Insulin Resistance; Male; Mice; Mice, Inbred C57BL; Obesity; Oxadiazoles; Plasminogen Activator Inhibitor 1; Ventricular Pressure

Topics: Angiotensin II Type 1 Receptor Blockers; Animals; Benzimidazoles; Insulin Resistance; Male; Obesity; Oxadiazoles

Aminoglycoside-mediated read-through of stop codons was recently demonstrated for a variety of diseases in vitro and in vivo. About 30 percent of human genetic diseases are the consequence of nonsense mutations. Nonsense mutations in obesity-associated genes like the melanocortin 4 receptor (MC4R), expressed in the hypothalamus, show the impact of premature stop codons on energy homeostasis. Therefore, the MC4R could be a potential pharmaceutical target for obesity treatment and targeting MC4R stop mutations could serve as proof of principle for nonsense mutations in genes expressed in the brain. We investigated four naturally occurring nonsense mutations in the MC4R (W16X, Y35X, E61X, Q307X) located at different positions in the receptor for aminoglycoside-mediated functional rescue in vitro. We determined localization and amount of full-length protein before and after aminoglycoside treatment by fluorescence microscopy, cell surface and total enzyme linked immunosorbent assay (ELISA). Signal transduction properties were analyzed by cyclic adenosine monophosphate (cAMP) assays after transient transfection of MC4R wild type and mutant receptors into COS-7 cells. Functional rescue of stop mutations in the MC4R is dependent on: (i) triplet sequence of the stop codon, (ii) surrounding sequence, (iii) location within the receptor, (iv) applied aminoglycoside and ligand. Functional rescue was possible for W16X, Y35X (N-terminus), less successful for Q307X (C-terminus) and barely feasible for E61X (first transmembrane domain). Restoration of full-length proteins by PTC124 could not be confirmed. Future pharmaceutical applications must consider the potency of aminoglycosides to restore receptor function as well as the ability to pass the blood-brain barrier.

Topics: Aminoglycosides; Blood-Brain Barrier; Codon, Nonsense; Codon, Terminator; Energy Metabolism; Female; Humans; Male; Obesity; Oxadiazoles; Receptor, Melanocortin, Type 4; Signal Transduction

1. Because the development of adipose tissue involves remodelling of the extracellular matrix (ECM), which requires matrix metalloproteinase (MMP) activity, we examined whether MMP inhibitors may have the potential to affect adipose tissue mass in obese mice. 2. Administration of the relatively gelatinase-specific MMP inhibitor tolylsam ((R)-3-methyl-2-[4-(3-p-tolyl-[1,2,4]oxadiazol-5-yl)-benzenesulphonylamino]-butyric acid; 100 mg/kg per day) for 7 weeks to obese wild-type mice on a high-fat diet resulted in significantly lower bodyweight (P < 0.05), lower subcutaneous (SC) and gonadal (GON) adipose tissue mass (both P < 0.05) and smaller adipocytes in both SC (P < 0.005) and GON (P < 0.0005) adipose tissues. 3. Magnetic resonance imaging confirmed a lower total body fat content in tolylsam-treated mice (P < 0.0005). In addition, tolylsam treatment of wild-type mice was associated with a marked enhancement in metabolic rate. 4. Electron microscopy analysis of tissue sections at the end of the 7 week feeding period revealed significantly higher collagen accumulation in the ECM of SC adipose tissues of tolylsam-treated mice (P < 0.001). 5. Thus, the relatively gelatinase-specific MMP inhibitor tolylsam has the potential to affect fat tissue growth in obese mice.

Topics: Adipose Tissue; Animals; Body Weight; Diet, High-Fat; Male; Matrix Metalloproteinase 2; Matrix Metalloproteinase 9; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Oxadiazoles; Sulfonamides

A novel series of DGAT-1 inhibitors was discovered from an oxadiazole amide high throughput screening (HTS) hit. Optimisation of potency and ligand lipophilicity efficiency (LLE) resulted in a carboxylic acid containing clinical candidate 53 (AZD3988), which demonstrated excellent DGAT-1 potency (0.6 nM), good pharmacokinetics and pre-clinical in vivo efficacy that could be rationalised through a PK/PD relationship.

Topics: Animals; Diabetes Mellitus; Diacylglycerol O-Acyltransferase; Dogs; Drug Design; Drug Evaluation, Preclinical; Enzyme Inhibitors; Half-Life; High-Throughput Screening Assays; Humans; Hypoglycemic Agents; Ligands; Mice; Obesity; Oxadiazoles; Quantitative Structure-Activity Relationship; Rats

Hypertension often coexists with insulin resistance. However, most metabolic effects of the antihypertensive agents have been investigated in nomotensive animals, in which different conclusions may arise. We investigated the metabolic effects of the new angiotensin II type 1 receptor blocker azilsartan using the obese Koletsky rats superimposed on the background of the spontaneously hypertensive rats.. Male Koletsky rats were treated with azilsartan (2 mg/kg/day) over 3 weeks. Blood pressure was measured by tail-cuff. Blood biochemical and hormonal parameters were determined by enzymatic or ELISA methods. Gene expression was assessed by RT-PCR.. In Koletsky rats, azilsartan treatment lowered blood pressure, basal plasma insulin concentration and the homeostasis model assessment of insulin resistance index, and inhibited over-increase of plasma glucose and insulin concentrations during oral glucose tolerance test. These effects were accompanied by decreases in both food intake and body weight (BW) increase. Although two treatments showed the same effect on BW gain, insulin sensitivity was higher after azilsartan treatment than pair-feeding. Azilsartan neither affected plasma concentrations of triglyceride and free fatty acids, nor increased adipose mRNA levels of peroxisome proliferator-activated receptor (PPAR)γ and its target genes such as adiponectin, aP2. In addition, azilsartan downregulated 11β-hydroxysteroid dehydrogenase type 1 expression.. These results show the insulin-sensitizing effect of azilsartan in obese Koletsky rats. This effect is independent of decreases in food intake and BW increase or of the activation of adipose PPARγ. Our findings indicate the possible usefulness of azilsartan in the treatment of metabolic syndrome.

Topics: Animals; Antihypertensive Agents; Benzimidazoles; Blood Glucose; Blood Pressure; Enzyme-Linked Immunosorbent Assay; Hypertension; Insulin; Insulin Resistance; Male; Obesity; Oxadiazoles; Polymerase Chain Reaction; PPAR gamma; Rats; Rats, Inbred SHR

Since the CB1 receptor antagonist SR141716 (rimonabant) was reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target in the treatment of obesity. Several series of derivatives based on diarylimidazolyl oxadiazole and thiadiazole scaffolds were synthesized and tested for CB1 receptor binding affinity. SAR studies directed toward the optimization of imidazole scaffolds resulted in the discovery of 10s which showed highest potency for CB1 receptor binding affinity (IC(50)=1.91nM) prepared to date.

Topics: Animals; Imidazoles; Inhibitory Concentration 50; Obesity; Oxadiazoles; Rats; Receptor, Cannabinoid, CB1; Structure-Activity Relationship; Thiadiazoles

Cannabinoid CB-1 receptors have been the focus of extensive studies since the first clinical results of rimonabant (SR141716) for the treatment of obesity and obesity-related metabolic disorders were reported in 2001. To further evaluate the properties of CB receptors, we have designed and efficiently prepared a series of oxadiazole-diarylpyrazole 4-carboxamides. Six of the new compounds which displayed high in vitro CB1 binding affinities were assayed for binding to CB2 receptor. Noticeably, 5-(4-bromophenyl)-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-(2,4-dichlorophenyl)-N-phenyl-1H-pyrazole-4-carboxamide (12q) and 5-(4-bromophenyl)-3-(5-tert-butyl-1,3,4-oxadiazol-2-yl)-1-(2,4-dichlorophenyl)-N-(pyridin-2-yl)-1H-pyrazole-4-carboxamide (12r) demonstrated good binding affinity and decent selectivity for CB1 receptor (IC(50) = 1.35 nM, CB2/CB1 = 286 for 12q; IC(50) = 1.46 nM, CB2/CB1 = 256 for 12r).

Topics: Animals; Anti-Obesity Agents; CHO Cells; Cricetinae; Cricetulus; Inhibitory Concentration 50; Ligands; Obesity; Oxadiazoles; Pyrazoles; Receptor, Cannabinoid, CB1; Structure-Activity Relationship; Transfection

Hologram QSAR studies were conducted on a series of 60 training set of cannabinoid-1 receptor (CB(1)) antagonists. Significant cross-validated correlation coefficients (q(2)=0.763) and noncross-validated correlation coefficients (r(2)=0.897) were obtained. The model was then employed to predict the biological activities of 15 test set compounds, and a good agreement between the experimental and predicted values was verified exhibiting a powerful predictable capability of this model (q(pred)(2)=0.868). Contribution map shows that 1,2,4-trizole and cyclopropane moieties make big contributions for the activities. Both the HQSAR model and analysis from the contribution map should be useful for the further design of novel structurally related CB(1) antagonists.

Topics: Cyclopropanes; Drug Design; Ligands; Obesity; Oxadiazoles; Quantitative Structure-Activity Relationship; Receptor, Cannabinoid, CB1; Triazoles

Since the cannabinoid receptor 1 (CB1) antagonist SR141716 (rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity.. In the present study, biarylpyrazole analogues based on a sulfur-containing pyrazole core coupled with 1,3,4-oxadiazole and 1,3,4-thiadiazole were synthesized and assayed for rat CB1 receptor binding affinity.. The structure-activity relationship studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole or 1,3,4-thiadiazole rings led to four novel CB1 antagonists with IC(50) values of approximately 1 nM for the rat CB1 receptor binding. Among these derivatives, we identified trifluoromethylcyclobutyl analogues 19e and 19l as promising precandidates for the development as anti-obesity agents.

Topics: Administration, Oral; Animals; Anti-Obesity Agents; Binding Sites; Biological Availability; Computer Simulation; Humans; Mice; Obesity; Oxadiazoles; Pyrazoles; Rats; Receptor, Cannabinoid, CB1; Structure-Activity Relationship; Thiadiazoles

Since the CB1 cannabinoid receptor antagonist 1 (SR141716, rimonabant) was previously reported to modulate food intake, CB1 antagonism has been considered as a new therapeutic target for the treatment of obesity. In the present study, biarylpyrazole analogues based on a pyrazole core coupled with 1,3,4-oxadiazole were synthesized and tested for CB1 receptor binding affinity. Thorough SAR studies to optimize pyrazole substituents as well as 1,3,4-oxadiazole ring led to several novel CB1 antagonists with IC(50) approximately 1 nM for the CB1 receptor binding. Among these analogues, we identified 2-(4-((1H-1,2,4-triazol-1-yl)methyl)-5-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-pyrazol-3-yl)-5-(1-(trifluoromethyl)cyclopropyl)-1,3,4-oxadiazole 43c as a promising precandidate for the development as an antiobesity agent.

Topics: Administration, Oral; Animals; Biological Availability; Computer Simulation; Crystallography, X-Ray; Dose-Response Relationship, Drug; Humans; Male; Mice; Mice, Inbred C57BL; Models, Chemical; Models, Molecular; Molecular Structure; Obesity; Oxadiazoles; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Stereoisomerism; Structure-Activity Relationship

The novel hypoglycemic agent YM440 ((Z)-1,4-bis{4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl] phenoxy}but-2-ene) is a ligand of the peroxisome proliferator-activated receptor (PPAR) gamma. YM440 has unique pharmacological profiles both in vitro and in vivo, but, it is not clear whether the compound has a significant effect on hepatic or peripheral insulin response throughout the body. The aim of this study is to examine the effects of YM440 on hepatic and peripheral insulin resistance in Zucker fatty (ZF) rats using the euglycemic-hyperinsulinaemic clamp technique. Treatment of ZF rats with YM440 (300 mg/kg per day) for 2 weeks significantly decreased plasma concentrations of glucose and insulin without inducing obesity. YM440 caused a 2-fold increase in the glucose infusion rate during euglycemic clamping compared with the vehicle control. YM440 also decreased the percent change in hepatic glucose production rate caused by intravenous insulin infusion in ZF rats. YM440 had no significant effect on the glucose disposal rate. These results indicate that YM440 ameliorates hepatic, but not peripheral insulin resistance in ZF rats. These findings strongly suggest that the main target organ of YM440 is the liver, unlike other PPARgamma agonist.

Topics: Algorithms; Animals; Blood Glucose; Body Weight; Drug Evaluation, Preclinical; Eating; Glucose; Glucose Clamp Technique; Hypoglycemic Agents; Infusions, Intravenous; Insulin; Insulin Resistance; Liver; Male; Molecular Structure; Obesity; Oxadiazoles; PPAR gamma; Rats; Rats, Zucker; Time Factors; Tritium

The novel hypoglycemic agent, YM440 ((Z)-1,4-bis{4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl) methyl] phenoxy}but-2-ene) is a ligand of the peroxisome proliferator-activated receptor, (PPAR) gamma. YM440 has been shown to counteract insulin resistance in diabetic rodent models. However, it is not clear whether this compound has a significant effect on hyperlipidemia in vivo. Hyperlipidemia has been reported to be a risk factor for the early development of renal disease. The aim of this study is to examine the effects of chronic treatment with YM440 on hyperlipidemia and renal injury in obese Zucker fatty (ZF) rats. Treatment of 8-week-old ZF rats with YM440 (100 mg/kg/day) for 16 weeks decreased plasma triglyceride and cholesterol concentrations. YM440 markedly reduced the rate of progression of both albuminuria and proteinuria. YM440 normalized urinary N-acetyl-beta-D-glucosaminidase (NAG) activity, which is a marker for renal proximal tubular damage, and ameliorated the rise in systolic blood pressure compared to the vehicle control. YM440 also blocked the development of nephromegaly. Histological analyses revealed that both glomerular area expansion and tubular cast accumulation gradually lessened in YM440-treated ZF rats. Regression analyses between the plasma triglyceride levels and the renal parameters (urinary protein excretion and albumin excretion) indicated that the renal parameters correlated positively with the plasma triglyceride levels. In conclusion, the hypolipidemic effects of YM440 prevent renal injury in ZF rats. YM440 might be useful for preventing the early development of diabetic nephropathy in subjects with type 2 diabetes by ameliorating metabolic control problems.

Topics: Acetylglucosaminidase; Albuminuria; Animals; Blood Glucose; Blood Pressure; Blood Urea Nitrogen; Body Weight; Cholesterol; Diabetes Mellitus, Type 2; Diabetic Nephropathies; Hypoglycemic Agents; Insulin; Kidney; Kidney Function Tests; Male; Obesity; Organ Size; Oxadiazoles; Rats; Rats, Zucker; Triglycerides

Using a glucose clamp, we had shown that YM440, (Z)-1,4-bis[4-[(3,5-dioxo-1,2,4-oxadiazolidin-2-yl)methyl]phenoxy]but-2-ene, reduced the increased hepatic glucose output in obese Zucker rats. We further examined effects of YM440 on 14C-incorporation from [14C]bicarbonate into blood glucose via gluconeogenesis, and on gluconeogenic enzymatic activities. Fed obese Zucker rats showed a 4-fold increase of 14C-incorporation into blood glucose compared to that in lean rats. Glucose-6-phosphatase and fructose-1,6-bisphosphatase activities in obese rats were increased 1.4-fold and 1.6-fold compared with lean rats. YM440 (300 mg/kg for 2 weeks) decreased 14C-incorporation into blood glucose by 29% in obese rats. Glucose-6-phosphatase but not fructose-1,6-bisphosphatase activity was reduced by YM440 and closely correlated with 14C-incorporation into blood glucose, indicating a key role for glucose-6-phosphatase in hepatic glucose output. These results suggest that the increased gluconeogenesis in obese rats is mainly due to the increased activities of glucose-6-phosphatase and fructose-1,6-bisphosphatase and that YM440 suppresses hepatic glucose output by reducing glucose-6-phosphatase activity.

Topics: Animals; Blood Glucose; Fructose-Bisphosphatase; Gluconeogenesis; Glucose; Glucose Clamp Technique; Glucose-6-Phosphatase; Hypoglycemic Agents; Liver; Male; Obesity; Oxadiazoles; Rats; Rats, Zucker