Exploration and Development of PPAR Modulators in Health and Disease : an Update of Clinical Evidence
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The Antidiabetic Drug Lobeglitazone Has the Potential to Inhibit PTP1B T Activity ⁎ Ruth F
Bioorganic Chemistry 100 (2020) 103927 Contents lists available at ScienceDirect Bioorganic Chemistry journal homepage: www.elsevier.com/locate/bioorg The antidiabetic drug lobeglitazone has the potential to inhibit PTP1B T activity ⁎ Ruth F. Rochaa, Tiago Rodriguesc, Angela C.O. Menegattia,b, , Gonçalo J.L. Bernardesc,d, Hernán Terenzia a Centro de Biologia Molecular Estrutural, Departamento de Bioquímica, Universidade Federal de Santa Catarina, Campus Trindade, 88040-900 Florianópolis, SC, Brazil b Universidade Federal do Piauí, CPCE, 64900-000 Bom Jesus, PI, Brazil c Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Avenida Professor Egas Moniz, 1649-028 Lisbon, Portugal d Department of Chemistry, University of Cambridge, Lensfield Road, CB2 1EW Cambridge, UK ARTICLE INFO ABSTRACT Keywords: Protein tyrosine phosphatase 1B (PTP1B) is considered a potential therapeutic target for the treatment of type 2 Thiazolidinediones diabetes mellitus (T2DM), since this enzyme plays a significant role to down-regulate insulin and leptin sig- Lobeglitazone nalling and its over expression has been implicated in the development of insulin resistance, T2DM and obesity. PPAR-γ Some thiazolidinediones (TZD) derivatives have been reported as promising PTP1B inhibitors with anti hy- PTP1B perglycemic effects. Recently, lobeglitazone, a new TZD, was described as an antidiabetic drug that targetsthe Non-competitive inhibitors PPAR-γ (peroxisome γ proliferator-activated receptor) pathway, but no information on its effects on PTP1B have been reported to date. We investigated the effects of lobeglitazone on PTP1B activity in vitro. Surprisingly, lobeglitazone led to moderate inhibition on PTP1B (IC50 42.8 ± 3.8 µM) activity and to a non-competitive reversible mechanism of action. -
Design Novel Dual Agonists for Treating Type-2 Diabetes by Targeting Peroxisome Proliferator-Activated Receptors with Core Hopping Approach
Design Novel Dual Agonists for Treating Type-2 Diabetes by Targeting Peroxisome Proliferator-Activated Receptors with Core Hopping Approach Ying Ma1., Shu-Qing Wang1,3*., Wei-Ren Xu2, Run-Ling Wang1*, Kuo-Chen Chou3 1 Tianjin Key Laboratory on Technologies Enabling Development of Clinical Therapeutics and Diagnostics (Theranostics), School of Pharmacy, Tianjin Medical University, Tianjin, China, 2 Tianjin Institute of Pharmaceutical Research (TIPR), Tianjin, China, 3 Gordon Life Science Institute, San Diego, California, United States of America Abstract Owing to their unique functions in regulating glucose, lipid and cholesterol metabolism, PPARs (peroxisome proliferator- activated receptors) have drawn special attention for developing drugs to treat type-2 diabetes. By combining the lipid benefit of PPAR-alpha agonists (such as fibrates) with the glycemic advantages of the PPAR-gamma agonists (such as thiazolidinediones), the dual PPAR agonists approach can both improve the metabolic effects and minimize the side effects caused by either agent alone, and hence has become a promising strategy for designing effective drugs against type-2 diabetes. In this study, by means of the powerful ‘‘core hopping’’ and ‘‘glide docking’’ techniques, a novel class of PPAR dual agonists was discovered based on the compound GW409544, a well-known dual agonist for both PPAR-alpha and PPAR- gamma modified from the farglitazar structure. It was observed by molecular dynamics simulations that these novel agonists not only possessed the same function as GW409544 did in activating PPAR-alpha and PPAR-gamma, but also had more favorable conformation for binding to the two receptors. It was further validated by the outcomes of their ADME (absorption, distribution, metabolism, and excretion) predictions that the new agonists hold high potential to become drug candidates. -
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. -
Combination Treatment with Pioglitazone and Fenofibrate
179 Combination treatment with pioglitazone and fenofibrate attenuates pioglitazone-mediated acceleration of bone loss in ovariectomized rats Rana Samadfam, Malaika Awori, Agnes Be´nardeau1, Frieder Bauss2, Elena Sebokova1, Matthew Wright1 and Susan Y Smith Charles River Laboratories, 22022 Transcanadienne, Senneville, Montre´al, Que´bec, Canada H9X 3R3 1F. Hoffmann-La Roche AG, Basel, CH-4070 Switzerland 2Roche Diagnostics GmbH, Penzberg, DE-82377 Germany (Correspondence should be addressed to S Y Smith; Email: [email protected]) Abstract Peroxisome proliferator-activated receptor (PPAR) g ago- mineral content (w45%) and bone mineral density (BMD; nists, such as pioglitazone (Pio), improve glycemia and lipid w60%) at the lumbar spine. Similar effects of treatments were profile but are associated with bone loss and fracture risk. Data observed at the femur, most notably at sites rich in trabecular regarding bone effects of PPARa agonists (including bone. At the proximal tibial metaphysis, concomitant fenofibrate (Feno)) are limited, although animal studies treatment with PioCFeno prevented Pio exacerbation of suggest that Feno may increase bone mass. This study ovariectomy-induced loss of trabecular bone, resulting in investigated the effects of a 13-week oral combination BMD values in the PioCFeno group comparable to OVX treatment with Pio (10 mg/kg per day)CFeno (25 mg/kg controls. Discontinuation of Pio or Feno treatment of per day) on body composition and bone mass parameters OVX rats was associated with partial reversal of effects on compared with Pio or Feno alone in adult ovariectomized bone loss or bone mass gain, respectively, while values in the (OVX) rats, with a 4-week bone depletion period, followed PioCFeno group remained comparable to OVX controls. -
Comparative Transcriptional Network Modeling of Three PPAR-A/C Co-Agonists Reveals Distinct Metabolic Gene Signatures in Primary Human Hepatocytes
Comparative Transcriptional Network Modeling of Three PPAR-a/c Co-Agonists Reveals Distinct Metabolic Gene Signatures in Primary Human Hepatocytes Rene´e Deehan1, Pia Maerz-Weiss2, Natalie L. Catlett1, Guido Steiner2, Ben Wong1, Matthew B. Wright2*, Gil Blander1¤a, Keith O. Elliston1¤b, William Ladd1, Maria Bobadilla2, Jacques Mizrahi2, Carolina Haefliger2, Alan Edgar{2 1 Selventa, Cambridge, Massachusetts, United States of America, 2 F. Hoffmann-La Roche AG, Basel, Switzerland Abstract Aims: To compare the molecular and biologic signatures of a balanced dual peroxisome proliferator-activated receptor (PPAR)-a/c agonist, aleglitazar, with tesaglitazar (a dual PPAR-a/c agonist) or a combination of pioglitazone (Pio; PPAR-c agonist) and fenofibrate (Feno; PPAR-a agonist) in human hepatocytes. Methods and Results: Gene expression microarray profiles were obtained from primary human hepatocytes treated with EC50-aligned low, medium and high concentrations of the three treatments. A systems biology approach, Causal Network Modeling, was used to model the data to infer upstream molecular mechanisms that may explain the observed changes in gene expression. Aleglitazar, tesaglitazar and Pio/Feno each induced unique transcriptional signatures, despite comparable core PPAR signaling. Although all treatments inferred qualitatively similar PPAR-a signaling, aleglitazar was inferred to have greater effects on high- and low-density lipoprotein cholesterol levels than tesaglitazar and Pio/Feno, due to a greater number of gene expression changes in pathways related to high-density and low-density lipoprotein metabolism. Distinct transcriptional and biologic signatures were also inferred for stress responses, which appeared to be less affected by aleglitazar than the comparators. In particular, Pio/Feno was inferred to increase NFE2L2 activity, a key component of the stress response pathway, while aleglitazar had no significant effect. -
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. -
Advances in Hepatology
ADVANCES IN HEPATOLOGY Current Developments in the Treatment of Hepatitis and Hepatobiliary Disease Hepatology Section Editor: Eugene R. Schiff, MD Novel Therapies for Cholestatic Liver Disease Cynthia Levy, MD Professor of Medicine Arthur Hertz Chair in Liver Diseases Associate Director, Schiff Center for Liver Diseases Division of Hepatology University of Miami Miller School of Medicine Miami, Florida G&H Currently, how is cholestatic liver G&H What are the limitations of the therapies disease in adults typically treated? currently being used? CL Cholestatic liver disease in adults mainly consists of CL Up to 40% of patients with PBC may not respond to primary biliary cholangitis (PBC) and primary sclerosing UDCA therapy, meaning that they will not have signifi- cholangitis (PSC). For PBC, the traditional first-line treat- cant biochemical improvement in alkaline phosphatase, ment is ursodeoxycholic acid (UDCA), starting at a dose which will remain elevated above 1.5 or 2 times the upper of 13 to 15 mg/kg/day. In May 2016, obeticholic acid limit of normal. In addition, in the PBC clinical trials for (Ocaliva, Intercept Pharmaceuticals) was approved by the obeticholic acid, only half of the patients met the primary US Food and Drug Administration (FDA) for second- endpoint. Furthermore, as previously mentioned, there is line treatment of PBC patients who either do not respond no FDA-approved treatment for PSC. Therefore, there are to UDCA therapy or who are intolerant of it. Dosing for unmet needs for PBC and PSC treatment, which have led noncirrhotic or well-compensated cirrhotic patients is 5 to a plethora of ongoing clinical trials exploring drugs of mg daily, which can be increased to 10 mg daily after 3 various mechanisms of action. -
Us 2018 / 0296525 A1
UN US 20180296525A1 ( 19) United States (12 ) Patent Application Publication (10 ) Pub. No. : US 2018/ 0296525 A1 ROIZMAN et al. ( 43 ) Pub . Date: Oct. 18 , 2018 ( 54 ) TREATMENT OF AGE - RELATED MACULAR A61K 38 /1709 ( 2013 .01 ) ; A61K 38 / 1866 DEGENERATION AND OTHER EYE (2013 . 01 ) ; A61K 31/ 40 ( 2013 .01 ) DISEASES WITH ONE OR MORE THERAPEUTIC AGENTS (71 ) Applicant: MacRegen , Inc ., San Jose , CA (US ) (57 ) ABSTRACT ( 72 ) Inventors : Keith ROIZMAN , San Jose , CA (US ) ; The present disclosure provides therapeutic agents for the Martin RUDOLF , Luebeck (DE ) treatment of age - related macular degeneration ( AMD ) and other eye disorders. One or more therapeutic agents can be (21 ) Appl. No .: 15 /910 , 992 used to treat any stages ( including the early , intermediate ( 22 ) Filed : Mar. 2 , 2018 and advance stages ) of AMD , and any phenotypes of AMD , including geographic atrophy ( including non -central GA and Related U . S . Application Data central GA ) and neovascularization ( including types 1 , 2 and 3 NV ) . In certain embodiments , an anti - dyslipidemic agent ( 60 ) Provisional application No . 62/ 467 ,073 , filed on Mar . ( e . g . , an apolipoprotein mimetic and / or a statin ) is used 3 , 2017 . alone to treat or slow the progression of atrophic AMD Publication Classification ( including early AMD and intermediate AMD ) , and / or to (51 ) Int. CI. prevent or delay the onset of AMD , advanced AMD and /or A61K 31/ 366 ( 2006 . 01 ) neovascular AMD . In further embodiments , two or more A61P 27 /02 ( 2006 .01 ) therapeutic agents ( e . g ., any combinations of an anti - dys A61K 9 / 00 ( 2006 . 01 ) lipidemic agent, an antioxidant, an anti- inflammatory agent, A61K 31 / 40 ( 2006 .01 ) a complement inhibitor, a neuroprotector and an anti - angio A61K 45 / 06 ( 2006 .01 ) genic agent ) that target multiple underlying factors of AMD A61K 38 / 17 ( 2006 .01 ) ( e . -
Classification Decisions Taken by the Harmonized System Committee from the 47Th to 60Th Sessions (2011
CLASSIFICATION DECISIONS TAKEN BY THE HARMONIZED SYSTEM COMMITTEE FROM THE 47TH TO 60TH SESSIONS (2011 - 2018) WORLD CUSTOMS ORGANIZATION Rue du Marché 30 B-1210 Brussels Belgium November 2011 Copyright © 2011 World Customs Organization. All rights reserved. Requests and inquiries concerning translation, reproduction and adaptation rights should be addressed to [email protected]. D/2011/0448/25 The following list contains the classification decisions (other than those subject to a reservation) taken by the Harmonized System Committee ( 47th Session – March 2011) on specific products, together with their related Harmonized System code numbers and, in certain cases, the classification rationale. Advice Parties seeking to import or export merchandise covered by a decision are advised to verify the implementation of the decision by the importing or exporting country, as the case may be. HS codes Classification No Product description Classification considered rationale 1. Preparation, in the form of a powder, consisting of 92 % sugar, 6 % 2106.90 GRIs 1 and 6 black currant powder, anticaking agent, citric acid and black currant flavouring, put up for retail sale in 32-gram sachets, intended to be consumed as a beverage after mixing with hot water. 2. Vanutide cridificar (INN List 100). 3002.20 3. Certain INN products. Chapters 28, 29 (See “INN List 101” at the end of this publication.) and 30 4. Certain INN products. Chapters 13, 29 (See “INN List 102” at the end of this publication.) and 30 5. Certain INN products. Chapters 28, 29, (See “INN List 103” at the end of this publication.) 30, 35 and 39 6. Re-classification of INN products. -
Disease Progression and Pharmacological Intervention in a Nutrient‑Defcient Rat Model of Nonalcoholic Steatohepatitis
Digestive Diseases and Sciences https://doi.org/10.1007/s10620-018-5395-7 ORIGINAL ARTICLE Disease Progression and Pharmacological Intervention in a Nutrient‑Defcient Rat Model of Nonalcoholic Steatohepatitis Kirstine S. Tølbøl1,3,4 · Birgit Stierstorfer2 · Jörg F. Rippmann2 · Sanne S. Veidal1 · Kristofer T. G. Rigbolt1 · Tanja Schönberger2 · Matthew P. Gillum4 · Henrik H. Hansen1 · Niels Vrang1 · Jacob Jelsing1 · Michael Feigh1 · Andre Broermann2 Received: 14 June 2018 / Accepted: 22 November 2018 © The Author(s) 2018 Abstract Background There is a marked need for improved animal models of nonalcoholic steatohepatitis (NASH) to facilitate the development of more efcacious drug therapies for the disease. Methods Here, we investigated the development of fbrotic NASH in male Wistar rats fed a choline-defcient L-amino acid- defned (CDAA) diet with or without cholesterol supplementation for subsequent assessment of drug treatment efcacy in NASH biopsy-confrmed rats. The metabolic profle and liver histopathology were evaluated after 4, 8, and 12 weeks of dieting. Subsequently, rats with biopsy-confrmed NASH were selected for pharmacological intervention with vehicle, elafbranor (30 mg/kg/day) or obeticholic acid (OCA, 30 mg/kg/day) for 5 weeks. Results The CDAA diet led to marked hepatomegaly and fbrosis already after 4 weeks of feeding, with further progression of collagen deposition and fbrogenesis-associated gene expression during the 12-week feeding period. Cholesterol supple- mentation enhanced the stimulatory efect of CDAA on gene transcripts associated with fbrogenesis without signifcantly increasing collagen deposition. Pharmacological intervention with elafbranor, but not OCA, signifcantly reduced stea- tohepatitis scores, and fbrosis-associated gene expression, however, was unable to prevent progression in fbrosis scores. -
Pemafibrate, a Novel Selective Peroxisome Proliferator-Activated
www.nature.com/scientificreports OPEN Pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, Received: 25 July 2016 Accepted: 11 January 2017 improves the pathogenesis in Published: 14 February 2017 a rodent model of nonalcoholic steatohepatitis Yasushi Honda1, Takaomi Kessoku1, Yuji Ogawa1, Wataru Tomeno1, Kento Imajo1, Koji Fujita1, Masato Yoneda1, Toshiaki Takizawa2, Satoru Saito1, Yoji Nagashima3 & Atsushi Nakajima1 The efficacy of peroxisome proliferator-activated receptorα -agonists (e.g., fibrates) against nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH) in humans is not known. Pemafibrate is a novel selective peroxisome proliferator-activated receptorα modulator that can maximize the beneficial effects and minimize the adverse effects of fibrates used currently. In a phase-2 study, pemafibrate was shown to improve liver dysfunction in patients with dyslipidaemia. In the present study, we first investigated the effect of pemafibrate on rodent models of NASH. Pemafibrate efficacy was assessed in a diet-induced rodent model of NASH compared with fenofibrate. Pemafibrate and fenofibrate improved obesity, dyslipidaemia, liver dysfunction, and the pathological condition of NASH. Pemafibrate improved insulin resistance and increased energy expenditure significantly. To investigate the effects of pemafibrate, we analysed the gene expressions and protein levels involved in lipid metabolism. We also analysed uncoupling protein 3 (UCP3) expression. Pemafibrate stimulated lipid turnover and upregulated UCP3 expression in the liver. Levels of acyl-CoA oxidase 1 and UCP3 protein were increased by pemafibrate significantly. Pemafibrate can improve the pathogenesis of NASH by modulation of lipid turnover and energy metabolism in the liver. Pemafibrate is a promising therapeutic agent for NAFLD/NASH. The incidence of nonalcoholic fatty liver disease (NAFLD) is increasing worldwide.