The Antidiabetic Drug Lobeglitazone Has the Potential to Inhibit PTP1B T Activity ⁎ Ruth F
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Dualism of Peroxisome Proliferator-Activated Receptor Α/Γ: a Potent Clincher in Insulin Resistance
AEGAEUM JOURNAL ISSN NO: 0776-3808 Dualism of Peroxisome Proliferator-Activated Receptor α/γ: A Potent Clincher in Insulin Resistance Mr. Ravikumar R. Thakar1 and Dr. Nilesh J. Patel1* 1Faculty of Pharmacy, Shree S. K. Patel College of Pharmaceutical Education & Research, Ganpat University, Gujarat, India. [email protected] Abstract: Diabetes mellitus is clinical syndrome which is signalised by augmenting level of sugar in blood stream, which produced through lacking of insulin level and defective insulin activity or both. As per worldwide epidemiology data suggested that the numbers of people with T2DM living in developing countries is increasing with 80% of people with T2DM. Peroxisome proliferator-activated receptors are a family of ligand-activated transcription factors; modulate the expression of many genes. PPARs have three isoforms namely PPARα, PPARβ/δ and PPARγ that play a central role in regulating glucose, lipid and cholesterol metabolism where imbalance can lead to obesity, T2DM and CV ailments. It have pathogenic role in diabetes. PPARα is regulates the metabolism of lipids, carbohydrates, and amino acids, activated by ligands such as polyunsaturated fatty acids, and drugs used as Lipid lowering agents. PPAR β/δ could envision as a therapeutic option for the correction of diabetes and a variety of inflammatory conditions. PPARγ is well categorized, an element of the PPARs, also pharmacological effective as an insulin resistance lowering agents, are used as a remedy for insulin resistance integrated with type- 2 diabetes mellitus. There are mechanistic role of PPARα, PPARβ/δ and PPARγ in diabetes mellitus and insulin resistance. From mechanistic way, it revealed that dual PPAR-α/γ agonist play important role in regulating both lipids as well as glycemic levels with essential safety issues. -
Corporate Presentation June 2019 Disclaimer
Corporate Presentation June 2019 Disclaimer Some of the statements contained in this presentation constitute forward-looking statements. Statements that are not historical facts are forward-looking statements. Forward-looking statements generally can be identified by the use of forward-looking terminology such as “may”, “will”, “expect”, “intend”, “estimate”, “anticipate”, “believe”, “continue” or similar terminology. These statements are based on the Company’s current strategy, plans, objectives, assumptions, estimates and projections. Investors should therefore not place undue reliance on those statements. The Company makes no representation, warranty or prediction that the results anticipated by such forward- looking statements will be achieved, and such forward-looking statements represent, in each case, only one of many possible scenarios and should not be viewed as the most likely or standard scenario. Forward-looking statements speak only as of the date that they are made and the Company does not undertake to update any forward-looking statements in light of new information or future events. Forward-looking statements involve inherent risks and uncertainties. The Company cautions that a number of important factors could cause actual results to differ materially from those contained in any forward-looking statement. 2 Well Diversified Mid-to-Late Stage Metabolic Pipeline for Large Market Opportunities Global partnerships secured for late stage clinical program in type 2 diabetes • Imeglimin: First in class oral drug candidate targeting -
CDR Clinical Review Report for Soliqua
CADTH COMMON DRUG REVIEW Clinical Review Report Insulin glargine and lixisenatide injection (Soliqua) (Sanofi-Aventis) Indication: adjunct to diet and exercise to improve glycemic control in adults with type 2 diabetes mellitus inadequately controlled on basal insulin (less than 60 units daily) alone or in combination with metformin. Service Line: CADTH Common Drug Review Version: Final (with redactions) Publication Date: January 2019 Report Length: 118 Pages Disclaimer: The information in this document is intended to help Canadian health care decision-makers, health care professionals, health systems leaders, and policy-makers make well-informed decisions and thereby improve the quality of health care services. While patients and others may access this document, the document is made available for informational purposes only and no representations or warranties are made with respect to its fitness for any particular purpose. The information in this document should not be used as a substitute for professional medical advice or as a substitute for the application of clinical judgment in respect of the care of a particular patient or other professional judgment in any decision-making process. The Canadian Agency for Drugs and Technologies in Health (CADTH) does not endorse any information, drugs, therapies, treatments, products, processes, or services. While care has been taken to ensure that the information prepared by CADTH in this document is accurate, complete, and up-to-date as at the applicable date the material was first published by CADTH, CADTH does not make any guarantees to that effect. CADTH does not guarantee and is not responsible for the quality, currency, propriety, accuracy, or reasonableness of any statements, information, or conclusions contained in any third-party materials used in preparing this document. -
Lobeglitazone
2013 International Conference on Diabetes and Metabolism Lobeglitazone, A Novel PPAR-γ agonist with balanced efficacy and safety Kim, Sin Gon. MD, PhD. Professor, Division of Endocrinology and Metabolism Department of Internal Medicine, Korea University College of Medicine. Disclosure of Financial Relationships This symposium is sponsored by Chong Kun Dang Pharmaceutical Corp. I have received lecture and consultation fees from Chong Kun Dang. Pros & Cons of PPAR-γ agonist Pros Cons • Good glucose lowering • Adverse effects • Durability (ADOPT) (edema, weight gain, • Insulin sensitizing CHF, fracture or rare effects (especially in MS, macular edema etc) NAFLD, PCOS etc) • Possible safety issues • Prevention of new- (risk of MI? – Rosi or onset diabetes (DREAM, bladder cancer? - Pio) ACT-NOW) • LessSo, hypoglycemiathere is a need to develop PPAR-γ • Few GI troubles agonist• Outcome with data balanced efficacy and safety (PROactive) Insulin Sensitizers : Several Issues Rosi, Peak sale ($3.3 billion) DREAM Dr. Nissen Dr. Nissen ADOPT META analysis BARI-2D (5,8) Rosi, lipid profiles RECORD 1994 1997 1999 2000 2002 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 Tro out d/t FDA, All diabetes hepatotoxicity drug CV safety Rosi (5) FDA, Black box Rosi, Rosi , CV safety warning - REMS in USA = no evidence - Europe out Pio (7) PIO, bladder cancer CKD 501 Lobeglitazone 2000.6-2004.6 2004.11-2007.1 2007.3-2008.10 2009.11-2011.04 Discovery& Preclinical study Phase I Phase II Phase III Developmental Strategy Efficacy • PPAR activity Discovery & Preclinical study • In vitro & vivo efficacy • Potent efficacy 2000.06 - 2004.06 Phase I 2004.11 - 2007.01 • In vitro screening • Repeated dose toxicity • Metabolites • Geno toxicity • Phase II CYP 450 • Reproductive toxicity 2007.03 - 2008.10 • DDI • Carcinogenic toxicity ADME Phase III Safety 2009.11 - 2011.04 CV Safety / (Bladder) Cancer / Liver Toxicity / Bone loss Lobeglitazone (Duvie) 1. -
AVANDIA (Rosiglitazone Maleate Tablets), for Oral Use Ischemic Cardiovascular (CV) Events Relative to Placebo, Not Confirmed in Initial U.S
HIGHLIGHTS OF PRESCRIBING INFORMATION ----------------------- WARNINGS AND PRECAUTIONS ----------------------- These highlights do not include all the information needed to use • Fluid retention, which may exacerbate or lead to heart failure, may occur. AVANDIA safely and effectively. See full prescribing information for Combination use with insulin and use in congestive heart failure NYHA AVANDIA. Class I and II may increase risk of other cardiovascular effects. (5.1) • Meta-analysis of 52 mostly short-term trials suggested a potential risk of AVANDIA (rosiglitazone maleate tablets), for oral use ischemic cardiovascular (CV) events relative to placebo, not confirmed in Initial U.S. Approval: 1999 a long-term CV outcome trial versus metformin or sulfonylurea. (5.2) • Dose-related edema (5.3) and weight gain (5.4) may occur. WARNING: CONGESTIVE HEART FAILURE • Measure liver enzymes prior to initiation and periodically thereafter. Do See full prescribing information for complete boxed warning. not initiate therapy in patients with increased baseline liver enzyme levels ● Thiazolidinediones, including rosiglitazone, cause or exacerbate (ALT >2.5X upper limit of normal). Discontinue therapy if ALT levels congestive heart failure in some patients (5.1). After initiation of remain >3X the upper limit of normal or if jaundice is observed. (5.5) AVANDIA, and after dose increases, observe patients carefully for signs • Macular edema has been reported. (5.6) and symptoms of heart failure (including excessive, rapid weight gain; • Increased incidence of bone fracture was observed in long-term trials. dyspnea; and/or edema). If these signs and symptoms develop, the heart (5.7) failure should be managed according to current standards of care. -
Comparison of Clinical Outcomes and Adverse Events Associated with Glucose-Lowering Drugs in Patients with Type 2 Diabetes: a Meta-Analysis
Online Supplementary Content Palmer SC, Mavridis D, Nicolucci A, et al. Comparison of clinical outcomes and adverse events associated with glucose-lowering drugs in patients with type 2 diabetes: a meta-analysis. JAMA. doi:10.1001/jama.2016.9400. eMethods. Summary of Statistical Analysis eTable 1. Search Strategies eTable 2. Description of Included Clinical Trials Evaluating Drug Classes Given as Monotherapy eTable 3. Description of Included Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin eTable 4. Description of Included Clinical Trials Evaluating Drug Classes Given as Triple Therapy When Added to Metformin Plus Sulfonylurea eTable 5. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Monotherapy eTable 6. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Dual Therapy Added to Metformin eTable 7. Risks of Bias in Clinical Trials Evaluating Drug Classes Given as Triple Therapy When Added to Metformin plus Sulfonylurea eTable 8. Estimated Global Inconsistency in Networks of Outcomes eTable 9. Estimated Heterogeneity in Networks eTable 10. Definitions of Treatment Failure Outcome eTable 11. Contributions of Direct Evidence to the Networks of Treatments eTable 12. Network Meta-analysis Estimates of Comparative Treatment Associations for Drug Classes Given as Monotherapy eTable 13. Network Meta-analysis Estimates of Comparative Treatment Associations for Drug Classes When Used in Dual Therapy (in Addition to Metformin) eTable 14. Network Meta-analysis Estimates of Comparative Treatment Effects for Drug Classes Given as Triple Therapy eTable 15. Meta-regression Analyses for Drug Classes Given as Monotherapy (Compared With Metformin) eTable 16. Subgroup Analyses of Individual Sulfonylurea Drugs (as Monotherapy) on Hypoglycemia eTable 17. -
The Effect of Rosiglitazone on Overweight Subjects with Type 1 Diabetes
Clinical Care/Education/Nutrition ORIGINAL ARTICLE The Effect of Rosiglitazone on Overweight Subjects With Type 1 Diabetes SUZANNE M. STROWIG, MSN, RN the potentially serious consequences of PHILIP RASKIN, MD excessive weight gain and insulin- induced hypoglycemia, investigators con- tinue to search for treatments that address both the treatment of insulin deficiency as well as other metabolic abnormalities that OBJECTIVE — To evaluate the safety and effectiveness of rosiglitazone in the treatment of are associated with diabetes (5). overweight subjects with type 1 diabetes. Insulin resistance, a metabolic abnor- mality common in type 2 diabetes, ap- RESEARCH DESIGN AND METHODS — A total of 50 adult type 1 diabetic subjects 2 pears to be present in individuals with with a baseline BMI Ն27 kg/m were randomly assigned in a double-blind fashion to take insulin and placebo (n ϭ 25) or insulin and rosiglitazone 4 mg twice daily (n ϭ 25) for a period of 8 type 1 diabetes, as well. Although insulin months. Insulin regimen and dosage were modified in all subjects to achieve near-normal resistance in type 2 diabetes is generally glycemic control. associated with obesity, hypertension, dyslipidemia, and other metabolic disor- RESULTS — Both groups experienced a significant reduction in HbA1c (A1C) level (rosigli- ders, studies have shown that overweight tazone: 7.9 Ϯ 1.3 to 6.9 Ϯ 0.7%, P Ͻ 0.0001; placebo: 7.7 Ϯ 0.8 to 7.0 Ϯ 0.9%, P ϭ 0.002) and as well as normal-weight adults with type a significant increase in weight (rosiglitazone: 97.2 Ϯ 11.8 to 100.6 Ϯ 16.0 kg, P ϭ 0.008; 1 diabetes can have peripheral and he- Ϯ Ϯ ϭ ϭ placebo: 96.4 12.2 to 99.1 15.0, P 0.016). -
AVANDIA® (Rosiglitazone Maleate) Tablets
PRESCRIBING INFORMATION AVANDIA® (rosiglitazone maleate) Tablets WARNING: CONGESTIVE HEART FAILURE ● Thiazolidinediones, including rosiglitazone, cause or exacerbate congestive heart failure in some patients (see WARNINGS). After initiation of AVANDIA, and after dose increases, observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, dyspnea, and/or edema). If these signs and symptoms develop, the heart failure should be managed according to current standards of care. Furthermore, discontinuation or dose reduction of AVANDIA must be considered. ● AVANDIA is not recommended in patients with symptomatic heart failure. Initiation of AVANDIA in patients with established NYHA Class III or IV heart failure is contraindicated. (See CONTRAINDICATIONS and WARNINGS.) DESCRIPTION AVANDIA (rosiglitazone maleate) is an oral antidiabetic agent which acts primarily by increasing insulin sensitivity. AVANDIA is used in the management of type 2 diabetes mellitus (also known as non-insulin-dependent diabetes mellitus [NIDDM] or adult-onset diabetes). AVANDIA improves glycemic control while reducing circulating insulin levels. Pharmacological studies in animal models indicate that rosiglitazone improves sensitivity to insulin in muscle and adipose tissue and inhibits hepatic gluconeogenesis. Rosiglitazone maleate is not chemically or functionally related to the sulfonylureas, the biguanides, or the alpha-glucosidase inhibitors. Chemically, rosiglitazone maleate is (±)-5-[[4-[2-(methyl-2- pyridinylamino)ethoxy]phenyl]methyl]-2,4-thiazolidinedione, (Z)-2-butenedioate (1:1) with a molecular weight of 473.52 (357.44 free base). The molecule has a single chiral center and is present as a racemate. Due to rapid interconversion, the enantiomers are functionally indistinguishable. The structural formula of rosiglitazone maleate is: The molecular formula is C18H19N3O3S•C4H4O4. -
The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development
International Journal of Molecular Sciences Review The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development Fan Hong 1,2, Pengfei Xu 1,*,† and Yonggong Zhai 1,2,* 1 Beijing Key Laboratory of Gene Resource and Molecular Development, College of Life Sciences, Beijing Normal University, Beijing 100875, China; [email protected] 2 Key Laboratory for Cell Proliferation and Regulation Biology of State Education Ministry, College of Life Sciences, Beijing Normal University, Beijing 100875, China * Correspondence: [email protected] (P.X.); [email protected] (Y.Z.); Tel.: +86-156-005-60991 (P.X.); +86-10-5880-6656 (Y.Z.) † Current address: Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA 15213, USA. Received: 22 June 2018; Accepted: 24 July 2018; Published: 27 July 2018 Abstract: Peroxisome proliferator-activated receptors (PPARs) are a well-known pharmacological target for the treatment of multiple diseases, including diabetes mellitus, dyslipidemia, cardiovascular diseases and even primary biliary cholangitis, gout, cancer, Alzheimer’s disease and ulcerative colitis. The three PPAR isoforms (α, β/δ and γ) have emerged as integrators of glucose and lipid metabolic signaling networks. Typically, PPARα is activated by fibrates, which are commonly used therapeutic agents in the treatment of dyslipidemia. The pharmacological activators of PPARγ include thiazolidinediones (TZDs), which are insulin sensitizers used in the treatment of type 2 diabetes mellitus (T2DM), despite some drawbacks. In this review, we summarize 84 types of PPAR synthetic ligands introduced to date for the treatment of metabolic and other diseases and provide a comprehensive analysis of the current applications and problems of these ligands in clinical drug discovery and development. -
Muraglitazar Bristol-Myers Squibb/Merck Daniella Barlocco
Muraglitazar Bristol-Myers Squibb/Merck Daniella Barlocco Address Originator Bristol-Myers Squibb Co University of Milan . Istituto di Chimica Farmaceutica e Tossicologica Viale Abruzzi 42 Licensee Merck & Co Inc 20131 Milano . Italy Status Pre-registration Email: [email protected] . Indications Metabolic disorder, Non-insulin-dependent Current Opinion in Investigational Drugs 2005 6(4): diabetes © The Thomson Corporation ISSN 1472-4472 . Actions Antihyperlipidemic agent, Hypoglycemic agent, Bristol-Myers Squibb and Merck & Co are co-developing Insulin sensitizer, PPARα agonist, PPARγ agonist muraglitazar, a dual peroxisome proliferator-activated receptor-α/γ . agonist, for the potential treatment of type 2 diabetes and other Synonym BMS-298585 metabolic disorders. In November 2004, approval was anticipated as early as mid-2005. Registry No: 331741-94-7 Introduction [579218], [579221], [579457], [579459]. PPARγ is expressed in Type 2 diabetes is a complex metabolic disorder that is adipose tissue, lower intestine and cells involved in characterized by hyperglycemia, insulin resistance and immunity. Activation of PPARγ regulates glucose and lipid defects in insulin secretion. The disease is associated with homeostasis, and triggers insulin sensitization [579216], older age, obesity, a family history of diabetes and physical [579218], [579458], [579461]. PPARδ is expressed inactivity. The prevalence of type 2 diabetes is increasing ubiquitously and has been found to be effective in rapidly, and the World Health Organization warns that, controlling dyslipidemia and cardiovascular diseases unless appropriate action is taken, the number of sufferers [579216]. PPARα agonists are used as potent hypolipidemic will double to over 350 million individuals by the year compounds, increasing plasma high-density lipoprotein 2030. Worryingly, it is estimated that only half of sufferers (HDL)-cholesterol and reducing free fatty acids, are diagnosed with the condition [www.who.int]. -
Insulin Secretion Volume of Cells
Société Médicale des Hôpitaux de Paris Le diabète quels enjeux ? 14 janvier 2011 DIABETE DE TYPE 2 NOUVELLES PISTES THÉRAPEUTIQUES Alain Ktorza Institut de Recherches Servier (IdRS) THE AIMS OF TREATMENT OF TYPE 2 DIABETES To prevent early death and improve quality of life To prevent micro- and macro vascular complications •Lipid profile •Cardiovascular Optimal glycemic control function •Atherogenes is CURRENT ORAL AGENTS USED IN THE TREATMENT OF TYPE 2 DIABETES THIAZOLIDINEDIONES SULFONYLUREAS INSULIN GLINIDES Pancreas INCRETINES (GLP-1) Gut White adipose tissue METFORMIN Muscle Liver ACARBOSE 6/7 different approaches. No one prevents the progressive deterioration of glycemic control FUNCTIONAL CELL MASS AND TYPE 2 DIABETES Decrease in cell mass in type 2 diabetic patients 40-60% Reduction compared to non diabetic patients Maclean, Ogilvie – 1955, Westermark, Wilander – 1978, Saito, et al, 1978,,,pp,1979, Klöppel, et al – 1985,,, Butler, et al – 2003,,, Yoon, et al – 2003, Deng et al - 2004 … Functionnal cell mass Insulin synthesis Number of cells Insulin secretion Volume of cells DihfilDecrease in the functional cell mass Progressive damage of glycemic control in type 2 diabetic patients POSSIBLE MECANISM OF CELL FAILURE IN TYPE 2 DIABETES Insulin resistance (b(obes ity, over fee ding, ph ysi cal li inacti tiitvity, geneti tifc fact ors?) N O -cell overstimulation Primary factors of R -cell stress dysfunction (genetic) M O H G Compensatory increase of Y L functional cell mass P Y E C R « Robust » cell « Susceptible » cell A -
Structural Basis for the Enhanced Anti-Diabetic Efficacy Of
www.nature.com/scientificreports OPEN Structural Basis for the Enhanced Anti-Diabetic Efcacy of Lobeglitazone on PPARγ Received: 9 October 2017 Jun Young Jang 1, Hwan Bae2, Yong Jae Lee3, Young Il Choi3, Hyun-Jung Kim4, Accepted: 4 December 2017 Seung Bum Park 2, Se Won Suh2, Sang Wan Kim 5 & Byung Woo Han 1 Published: xx xx xxxx Peroxisome proliferator-activated receptor γ (PPARγ) is a member of the nuclear receptor superfamily. It functions as a ligand-activated transcription factor and plays important roles in the regulation of adipocyte diferentiation, insulin resistance, and infammation. Here, we report the crystal structures of PPARγ in complex with lobeglitazone, a novel PPARγ agonist, and with rosiglitazone for comparison. The thiazolidinedione (TZD) moiety of lobeglitazone occupies the canonical ligand-binding pocket near the activation function-2 (AF-2) helix (i.e., helix H12) in ligand-binding domain as the TZD moiety of rosiglitazone does. However, the elongated p-methoxyphenol moiety of lobeglitazone interacts with the hydrophobic pocket near the alternate binding site of PPARγ. The extended interaction of lobeglitazone with the hydrophobic pocket enhances its binding afnity and could afect the cyclin- dependent kinase 5 (Cdk5)-mediated phosphorylation of PPARγ at Ser245 (in PPARγ1 numbering; Ser273 in PPARγ2 numbering). Lobeglitazone inhibited the phosphorylation of PPARγ at Ser245 in a dose-dependent manner and exhibited a better inhibitory efect on Ser245 phosphorylation than rosiglitazone did. Our study provides new structural insights into the PPARγ regulation by TZD drugs and could be useful for the discovery of new PPARγ ligands as an anti-diabetic drug, minimizing known side efects.