DOCSLIB.ORG

Current Pharma Research ISSN: 2230-7842 CPR 3(2), 2013, 846-854

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Current Pharma Research ISSN: 2230-7842 CPR 3(2), 2013, 846-854 Review Article Current Pharma Research ISSN: 2230-7842 CPR 3(2), 2013, 846-854. PPAR Dual Agonist: In Treatment of Type II Diabetes. *1Kishan Patel, 1R. N. Sharma, 1L. J. Patel, 2G. M. Patel 1S. K. Patel College of Pharmaceutical Education and Research, Ganpat University, Mehsana-Gozaria Highway, Kherva, Gujarat, India, 2K. B. Institute of Pharmaceutical Education and Research, Gandhinagar, Gujarat, India. Abstract Peroxisome proliferator-activated receptors (PPARs) are central regulators of lipoprotein metabolism and glucose homeostasis that are considered particularly useful for improving glycemic control and co morbidities in patients with type II diabetes mellitus. Clinical trials of PPAR-α agonists have demonstrated efficacy in reducing cardiovascular events; however, these benefits have been confined to subgroups of patients with low levels of high-density lipoprotein cholesterol or high levels of triglycerides. While activators of PPAR-γ reduce early atherosclerotic lesions and reduce cardiovascular events, these agents have the effect of increasing fluid retention in patients, which results in more hospitalizations for congestive heart failure. The PPAR α / γ dual agonists are developed to increase insulin sensitivity and simultaneously prevent diabetic cardiovascular complications. Such compounds are under clinical trials and proposed for treatment of type II diabetes with secondary cardiovascular complications. However, PPAR α / γ dual agonists such as muraglitazar, tesaglitazar and ragaglitazar have been noted to produce several cardiovascular risks and carcinogenicity, which raised number of questions about the clinical applications of dual agonists in diabetes and its associated complications. Therefore future studies of PPAR-γ agonists or dual PPAR-α/γ agonists will require further delineation of the risk profile to avoid adverse outcomes in susceptible patients. Key Words Peroxisome proliferated-activated receptors, Type II diabetes, Dual agonist. Introduction Identification of molecular atherosclerosis and diabetes. mechanisms of the transducer proteins Cardiovascular disorders are the most involved in metabolic and anabolic common cause of morbidity and pathways is crucial for understanding mortality in diabetes and their the energy homeostasis in the human prevalence is increasing constantly in body and to develop new therapeutic developing countries. Diabetes is a agents for the treatment of chronic metabolic disorder characterized by metabolic disorders such as, insulin resistance and reduced secretion of insulin and is associated *Corresponding Author: with cardiovascular pathologies such [email protected] as atherosclerosis, hypertension, 846 Kishan Patel et al., Current Pharma Research., Vol. 3(2), 2013, 846-854. endothelial dysfunction, cardiac PPARs (PPARα, PPARγ, PPARβ/δ) dysfunction and myocardial are transcription factors that regulate infarction. The peroxisome gene transcription by binding to proliferator-activated receptors specific DNA response elements upon (PPARs) are a group of nuclear ligand activation and receptor proteins that function as heterodimerization with the 9-cis transcription factors regulating the retinoic acid receptor. Ligand-induced expression of genes1. PPARs play conformational changes induce the essential roles in the regulation of recruitment of coactivators that cellular differentiation, development, transmit transcription activation and metabolism (carbohydrate, lipid, signals to basal transcriptional protein), and tumorigenesis2 of higher machinery6. Depending upon the organisms3, 4. activating ligand, different receptor Types of PPAR conformations are adopted, leading to To date, three major types of PPAR, differential coactivator recruitment encoded by separate genes, have been and subsequent downstream effects on identified; they are PPAR- α gene expression (Figure 2). Selective (NR1C1), PPAR- δ/ β (NR1C2) and modulation has been described both PPAR-γ (NR1C3). Functions of for PPARα (selective peroxisome PPARs and conditions that are the proliferator-activated receptor α targets of PPAR agonists are modulator [SPPARαM])7 and PPARγ summarized in Table 1. [SPPARγM]8, and could explain the Like other nuclear receptors, PPARs differences seen in biological activity are modular in structure and contain of ligands, even those belonging to the the following functional domains: same pharmacological class. Thus, the (A/B) N-terminal region selective modulator concept provides (C) DBD (DNA-binding a molecular approach to develop domain) ligands devoid of adverse effects, (D) flexible hinge region while maintaining the desirable 9 (E) LBD ( ligand binding biological efficacy . The gene domain) transcription mechanism is identical in (F) C-terminal region all PPAR subtypes. Important The DBD contains two zinc finger biological effects of each individual motifs, which bind to specific PPAR isoform are shown in Figure 3. sequences of DNA known as hormone PPAR Ligands: response elements when the receptor Chemical structures of some PPAR is activated. The LBD has an ligands are given below (Figure 4): extensive secondary structure PPARα AND PPARγ AS A DUAL consisting of 13 alpha helices and a AGONIST: beta sheet5. Natural and synthetic PPARα/γ dual agonists are new class ligands bind to the LBD, either of drugs, which have been developed activating or repressing the receptor. to target both PPARα and PPARγ simultaneously in order to produce synergistic anti diabetic and cardio 847 Kishan Patel et al., Current Pharma Research., Vol. 3(2), 2013, 846-854. protective effects. Simultaneous muraglitazar has efficiently reduced activation of PPARα and γ activators hemoglobin A1C and improved the might, through a complementary lipid profile in diabetic patients13. mechanism of action, alter the tissue However, the clinical study with distribution of fatty acids by muraglitazar was discontinued stimulating their uptake and utilization recently due to higher incidence of in adipose tissue, liver and skeletal edema and heart failure17. Tesaglitazar muscle (Figure 5). The recently has been shown to reduce investigated PPARα/γ dual agonists atherosclerosis in the LDL receptor are naveglitazar, netoglitazone, deficient mice probably by its direct muraglitazar, ragaglitazar, actions on the vessels18. Further, tesaglitazar, imiglitazar, MK 767, LY tesaglitazar has been suggested to 929 and LSN86210. The PPARα/γ have beneficial effects on both dual agonists are noted to reduce hyperglycemia and dyslipidemia19. triglycerides, raise cardioprotective However its development has been HDL levels and consequently improve terminated due to the elevated serum insulin sensitivity6,11–13. Treatment creatinine and associated decreases in with ragaglitazar significantly reduced glomerular filtration rate20. These blood pressure in spontaneously discouraging results with muraglitazar hypertensive rats and improved and tesaglitazar have raised a number endothelial function in Zucker of questions about the role of diabetic fatty (ZDF) rats when PPARα/γ dual agonists in diabetic compared with pioglitazone complications. The balanced binding treatment14. Moreover, it has been affinity of PPARα/γ dual agonists reported that treatment with DRF towards both the receptor subtypes is 2519, a PPAR α/γ dual agonist has necessary to give optimal biological resulted in better lipid profile and effects of both PPARα-mediated and enhanced aortic smooth muscle PPARγ-mediated actions. Supra relaxation in ZDF rats when compared therapeutic activation of PPARα or with rosiglitazone treatment15. These PPARγ may be associated with results exemplify the beneficial effects adverse effects such as of dual PPAR α/γ dual agonist in carcinogenesis, renal dysfunction, improving the cardiovascular risk fluid retention and heart failure21–23. factors. The PPARγ agonists are The muraglitazar has high affinity shown to increase adipogenesis and towards PPARγ and tesaglitazar body weight, whereas PPARα possesses more affinity towards agonists counteract these effects by PPARα20. Thus, the lack of balance in decreasing food intake and fat binding affinity may lead to supra- deposits in animals11, 16. Thus, therapeutic expression of the stronger increase in body weight observed with agonist which may cause adverse PPARγ treatment may not be effects. The clinical study in which associated with PPARα/γ dual dual PPARα/γ stimulation by means agonists. However, such effects are of concomitant administration of not clear in human situation. The fenofibrate and rosiglitazone 848 Kishan Patel et al., Current Pharma Research., Vol. 3(2), 2013, 846-854. improved atherogenic dyslipidemic under development to prevent the profile in patients with good diabetic cardiovascular complications. tolerability24. Hence, the future development of dual agonists with References selective and balanced PPARα/γ 1. Michalik L, Auwerx J, Berger activity may be appropriate and JP, Chatterjee VK, Glass CK, sensible option. One of the challenges Gonzalez FJ, Grimaldi PA, of the development of PPAR dual Kadowaki T, Lazar MA, agonists is that one single molecule O'Rahilly S, Palmer CN, has to cause the appropriate Plutzky J, Reddy JK, pharmacological profile by interaction Spiegelman BM, Staels B, with two or more different receptors Wahli W: "International Union that are expressed in two or more of Pharmacology. LXI. different sites of action. Peroxisome proliferator- activated receptors". Conclusion Pharmacol. Rev. 2006, 58 (4): Cardiovascular complications are
Load more

Recommended publications
  • Type 2 Diabetes Mellitus: a Review of Multi-Target Drugs
    Molecules 2020, 25, 1987 1 of 20 Review Type 2 Diabetes Mellitus: A Review of Multi-Target Drugs Angelica Artasensi, Alessandro Pedretti, Giulio Vistoli and Laura Fumagalli * Dipartimento di Scienze Farmaceutiche, University Degli Studi di Milano, 20133 Milano, Italy; [email protected] (A.A.); [email protected] (A.P.); [email protected] (G.V.) * Correspondence: [email protected]; Tel.: +39-02-5031-9303 Academic Editor: Massimo Bertinaria, Derek J. McPhee Received: 01 April 2020; Accepted: 21 April 2020; Published: 23 April 2020 Abstract: Diabetes Mellitus (DM) is a multi-factorial chronic health condition that affects a large part of population and according to the World Health Organization (WHO) the number of adults living with diabetes is expected to increase. Since type 2 diabetes mellitus (T2DM) is suffered by the majority of diabetic patients (around 90–95%) and often the mono-target therapy fails in managing blood glucose levels and the other comorbidities, this review focuses on the potential drugs acting on multi-targets involved in the treatment of this type of diabetes. In particular, the review considers the main systems directly involved in T2DM or involved in diabetes comorbidities. Agonists acting on incretin, glucagon systems, as well as on peroxisome proliferation activated receptors are considered. Inhibitors which target either aldose reductase and tyrosine phosphatase 1B or sodium glucose transporters 1 and 2 are taken into account. Moreover, with a view at the multi-target approaches for T2DM some phytocomplexes are also discussed. Keywords: diabetes mellitus; type 2 diabetes mellitus; multi-target compounds; multi-target drugs 1.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • NPY1R-Targeted Peptide-Mediated Delivery of a Dual PPAR&Alpha
    Original Article NPY1R-targeted peptide-mediated delivery of a dual PPARa/g agonist to adipocytes enhances adipogenesis and prevents diabetes progression Stefanie Wittrisch 1, Nora Klöting 2,**, Karin Mörl 1, Rima Chakaroun 2,3, Matthias Blüher 2,3,***, Annette G. Beck-Sickinger 1,* ABSTRACT Objective: PPARa/g dual agonists have been in clinical development for the treatment of metabolic diseases including type 2 diabetes and dyslipidemia. However, severe adverse side effects led to complications in clinical trials. As most of the beneficial effects rely on the compound activity in adipocytes, the selective targeting of this cell type is a cutting-edge strategy to develop safe anti-diabetic drugs. The goal of this study was to strengthen the adipocyte-specific uptake of the PPARa/g agonist tesaglitazar via NPY1R-mediated internalization. 7 34 Methods: NPY1R-preferring peptide tesaglitazar-[F ,P ]-NPY (tesa-NPY) was synthesized by a combination of automated SPPS and manual couplings. Following molecular and functional analyses for proof of concept, cell culture experiments were conducted to monitor the effects on adipogenesis. Mice treated with peptide drug conjugates or vehicle either by gavage or intraperitoneal injection were characterized phenotypically and metabolically. Histological analysis and transcriptional profiling of the adipose tissue were performed. 7 34 Results: In vitro studies revealed that the tesaglitazar-[F ,P ]-NPY conjugate selectively activates PPARg in NPY1R-expressing cells and enhances adipocyte differentiation and adiponectin expression in adipocyte precursor cells. In vivo studies using db/db mice demonstrated that the anti-diabetic activity of the peptide conjugate is as efficient as that of systemically administered tesaglitazar.
    [Show full text]
  • 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.
    [Show full text]
  • Thiazolidinedione Drugs Down-Regulate CXCR4 Expression on Human Colorectal Cancer Cells in a Peroxisome Proliferator Activated Receptor Á-Dependent Manner
    1215-1222 26/3/07 18:16 Page 1215 INTERNATIONAL JOURNAL OF ONCOLOGY 30: 1215-1222, 2007 Thiazolidinedione drugs down-regulate CXCR4 expression on human colorectal cancer cells in a peroxisome proliferator activated receptor Á-dependent manner CYNTHIA LEE RICHARD and JONATHAN BLAY Department of Pharmacology, Faculty of Medicine, Dalhousie University, Halifax, Nova Scotia, B3H 1X5, Canada Received October 26, 2006; Accepted December 4, 2006 Abstract. Peroxisome proliferator activated receptor (PPAR) Introduction Á is a nuclear receptor involved primarily in lipid and glucose metabolism. PPARÁ is also expressed in several cancer types, Peroxisome proliferator activated receptors (PPARs) are and has been suggested to play a role in tumor progression. nuclear hormone receptors that are involved primarily in PPARÁ agonists have been shown to reduce the growth of lipid and glucose metabolism (1). Upon ligand activation, colorectal carcinoma cells in culture and in xenograft models. these receptors interact with the retinoid X receptor (RXR) Furthermore, the PPARÁ agonist thiazolidinedione has been and bind to peroxisome proliferator response elements (PPREs), shown to reduce metastasis in a murine model of rectal cancer. leading to transcriptional regulation of target genes. Members Since the chemokine receptor CXCR4 has emerged as an of the thiazolidinedione class of antidiabetic drugs act as important player in tumorigenesis, particularly in the process ligands for PPARÁ (2), as does endogenously produced 15- 12,14 of metastasis, we sought to determine if PPARÁ agonists deoxy-¢ -prostaglandin J2 (15dPGJ2) (3). might act in part by reducing CXCR4 expression. We found In addition to regulation of glucose metabolism, PPARÁ that rosiglitazone, a thiazolidinedione PPARÁ agonist used appears also to be involved in tumorigenesis, although its primarily in the treatment of type 2 diabetes, significantly exact role has yet to be elucidated (4).
    [Show full text]
  • Possible Role of Rivoglitazone Thiazolidine Class of Drug As Dual
    Medical Hypotheses 131 (2019) 109305 Contents lists available at ScienceDirect Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy Possible role of rivoglitazone thiazolidine class of drug as dual-target therapeutic agent for bacterial infections: An in silico study T ⁎ Vidyasrilekha Yele , Niladri Saha, Afzal Azam Md Department of Pharmaceutical Chemistry, JSS College of Pharmacy, Ootacamund, JSS Academy of Higher Education & Research, Mysuru 643001, India ARTICLE INFO ABSTRACT Keywords: Infections due to resistant bacteria are the life-threatening and leading cause of mortality worldwide. The Rivoglitazone current therapy for bacterial infections includes treatment with various drugs and antibiotics. The misuse and ParE over usage of these antibiotics leads to bacterial resistance. There are several mechanisms by which bacteria MurE exhibit resistance to some antibiotics. These include drug inactivation or modification, elimination of antibiotics Docking through efflux pumps, drug target alteration, and modification of metabolic pathway. However, it is difficult to MM-GBSA treat infections caused by resistant bacteria by conventional existing therapy. In the present study binding af- Molecular dynamic simulations fi Anti-bacterial agent nities of some glitazones against ParE and MurE bacterial enzymes are investigated by in silico methods. As evident by extra-precision docking and binding free energy calculation (MM-GBSA) results, rivoglitazone ex- hibited higher binding affinity against both ParE and MurE enzymes compared to all other selected compounds. Further molecular dynamic (MD) simulations were performed to validate the stability of rivoglitazone/4MOT and rivoglitazone/4C13 complexes and to get insight into the binding mode of inhibitor. Thus, we hypothesize that structural modifications of the rivoglitazone scaffold can be useful for the development of an effective antibacterial agent.
    [Show full text]
  • Peroxisome Proliferator-Activated Receptors As Superior Targets to Treat Diabetic Disease, Design Strategies - Review Article
    Review article DOI: 10.4274/tjps.galenos.2021.70105 Peroxisome proliferator-activated receptors as superior targets to treat diabetic disease, design strategies - review article Diyabetik hastalığı tedavi etmek için üstün hedefler olarak peroksizom proliferatör ile aktive edilmiş reseptörler, tasarım stratejileri - inceleme makalesi Mohammed T Qaoud1, Ihab Al-masri2, Tijen Önkol1 1Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara- Turkey 2Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmacy, Al Azhar University, Gaza Strip, Palestine proof Corresponding Author Mohammed T Qaoud, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Gazi University, Ankara-Turkey [email protected] +90 552 634 15 56 https://orcid.org/0000-0002-9563-9493 09.12.2020 31.05.2021 09.06.2021 Abstract Thiazolidinedione (TZD), a class of drugs that are mainly used to control type II diabetes mellitus (T2DM), acts fundamentally as a ligand of peroxisome proliferator-activated receptors (PPARs). Besides activating pathways responsible for glycemic control via enhancing insulin sensitivity and lipid homeostasis, activating PPARs leads to exciting other pathways related to bone formation, inflammation, and cell proliferation. Unfortunately, this diverse effect via activating several pathways may show in some studies adverse health outcomes as osteological, hepatic, cardiovascular, and carcinogenic effects. Thus, an argent demand is present to find and develop new active and potent antiglycemic drugs for the treatment of T2DM. To achieve this goal, the structure of TZD for research is considered as a leading structure domain. This review would guide future research in the design of novel TZD derivatives through highlighting the general modifications conducted to the structure component of TZD scaffold affecting their potency, binding efficacy, and selectivity for the control of type II diabetes mellitus.
    [Show full text]
  • Tot-JNK 18S Patent Application Publication Mar
    US 2010.0075894A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0075894 A1 Hotamisligil et al. (43) Pub. Date: Mar. 25, 2010 (54) REDUCINGER STRESS IN THE TREATMENT A63L/92 (2006.01) OF OBESITY AND DABETES A 6LX 3/575 (2006.01) A63/04 (2006.01) (75) Inventors: Gökhan S. Hotamisligil, Wellesley, A6II 3/55 (2006.01) MA (US); Umut Ozcan, Brookline, A613/60 (2006.01) MA (US) A6IP3/10 (2006.01) A6IP3/04 (2006.01) Correspondence Address: A6IP 9/10 (2006.01) EDWARDSANGELL PALMER & DODGE LLP (s2 usic... 514/4; 435/7.2:436/86; 514/570; P.O. BOX SS874 514/169; 514/740: 514/171; 514/635: 514/165 BOSTON, MA 02205 (US) (57) ABSTRACT (73) Assignee: HARYARPN.YERSITY, Endoplasmic reticulum stress has been found to be associated ambridge, (US) with obesity. Therefore, agents that reduce or prevent ER (21) Appl. No.: 12/541,020 stress may be used to treat diseases associated with obesity including peripheral insulin resistance, hypergylcemia, and (22) Filed: Aug. 13, 2009 type 2 diabetes. Two compounds which have been shown to reduce ER stress and to reduce blood glucose levels include Related U.S. Application Data 4-phenyl butyric acid (PBA), tauroursodeoxycholic acid (TUDCA), and trimethylamine N-oxide (TMAO). Other (63) Continuation of application No. 1 1/227.497, filed on compounds useful in reducing ER stress are chemical chap Sep. 15, 2005, now abandoned. erones Such as trimethylamine N-oxide and glycerol. The (60) Provisional application No. 60/610,093, filed on Sep. E. invention provides methods of treating a subject suf 15, 2004.
    [Show full text]
  • Molecular Modeling Study of Pparγ Agonists: Dehydro-Di-Isoeugenol, Macelignan, Pioglitazone, Netoglitazone, and Rosiglitazone As Antidiabetic Drugs
    International Journal of Chemistry; Vol. 6, No. 2; 2014 ISSN 1916-9698 E-ISSN 1916-9701 Published by Canadian Center of Science and Education Molecular Modeling Study of PPARγ Agonists: Dehydro-Di-Isoeugenol, Macelignan, Pioglitazone, Netoglitazone, and Rosiglitazone as Antidiabetic Drugs Nyi Mekar Saptarini1, Febrina Amelia Saputri1 & Jutti Levita1 1 Faculty of Pharmacy, Padjadjaran University, West Java, Indonesia Correspondence: Nyi Mekar Saptarini, Faculty of Pharmacy, Padjadjaran University, Jl. Raya Bandung-Sumedang Km.21 Jatinangor Sumedang, West Java 45363, Indonesia. Tel: 62-815-607-8248. Fax: 62- 227-796-200. E-mail: [email protected] Received: February 23, 2014 Accepted: April 2, 2014 Online Published: April 14, 2014 doi:10.5539/ijc.v6n2p48 URL: http://dx.doi.org/10.5539/ijc.v6n2p48 Abstract The peroxisome proliferator-activated receptors (PPARs) are ligand-activated trasncription factors belonging to the nuclear receptor family. The objective of this study is to analyze the molecular aspects of PPARγ agonists which used to design of new antidiabetic drugs. The analysis method was comparing the interactions of ligands in the ligand binding domain of the PPARγ. This analysis showed that most known agonists of PPARγ interacted via hydrogen bond with Tyr473. Pioglitazone showed three hydrogen bonds with His323 and Tyr473. Netoglitazone showed four hydrogen bonds with Ser289, His323, His449, and Tyr473. Rosiglitazone showed five hydrogen bonds with Ser289, His323, His449, and Tyr473. AZ72, an agonist of PPARα and γ showed five hydrogen bonds with Ser289, His323, His449, and Tyr473. Molecular modeling was performed by redocking pioglitazone and rosiglitazone using AutoDock Vina. Docking showed that both pioglitazone (Ki 0.22 μM) and rosiglitazone (Ki 0.70 μM) occupied their origin sites and interacted with Tyr473.
    [Show full text]
  • Oral Anti-Diabetic Agents-Review and Updates
    British Journal of Medicine & Medical Research 5(2): 134-159, 2015, Article no.BJMMR.2015.016 ISSN: 2231-0614 SCIENCEDOMAIN international www.sciencedomain.org Oral Anti-Diabetic Agents-Review and Updates Patience O. Osadebe1, Estella U. Odoh2 and Philip F. Uzor1* 1Department of Pharmaceutical and Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Enugu State, 410001, Nigeria. 2Department of Pharmacognosy and Environmental Medicine, Faculty of Pharmaceutical Sciences, University of Nigeria, Nsukka, Enugu State, 410001, Nigeria. Authors’ contributions Author POO designed the study, participated in the literature search. Author EUO participated in designing the work and in searching the literature. Author PFU participated in designing the work, searched the literature and wrote the first draft of the manuscript. All authors read and approved the final manuscript. Article Information DOI:10.9734/BJMMR/2015/8764 Editor(s): (1) Mohamed Essa, Department of Food Science and Nutrition, Sultan Qaboos University, Oman. (2) Franciszek Burdan, Experimental Teratology Unit, Human Anatomy Department, Medical University of Lublin, Poland and Radiology Department, St. John’s Cancer Center, Poland. Reviewers: (1) Anonymous, Bushehr University of Medical, Iran. (2) Anonymous, Tehran University of Medical Sciences, Iran. (3) Anonymous, King Fahad Armed Forces Hospital, Saudi Arabia. (4) Awadhesh Kumar Sharma, Mlb Medical College, Jhansi, UP, India. Peer review History: http://www.sciencedomain.org/review-history.php?iid=661&id=12&aid=5985 Received 30th December 2013 Review Article Accepted 13th March 2014 Published 8th September 2014 ABSTRACT Diabetes is a chronic metabolic disorder with high mortality rate and with defects in multiple biological systems. Two major types of diabetes are recognized, type 1 and 2 with type 2 diabetes (T2D) being by far the more prevalent type.
    [Show full text]