DOCSLIB.ORG

Design, Synthesis, and Evaluation of Thiazolidinedione Derivatives Inhibiting Bcl-2/Bcl-Xl Or Ablating Androgen Receptor for the Treatment of Prostate Cancer

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Design, Synthesis, and Evaluation of Thiazolidinedione Derivatives Inhibiting Bcl-2/Bcl-Xl Or Ablating Androgen Receptor for the Treatment of Prostate Cancer DESIGN, SYNTHESIS, AND EVALUATION OF THIAZOLIDINEDIONE DERIVATIVES INHIBITING BCL-2/BCL-XL OR ABLATING ANDROGEN RECEPTOR FOR THE TREATMENT OF PROSTATE CANCER DISSERTATION Presented in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy in the Graduate School of The Ohio State University By Jian Yang, M.S. * * * * * The Ohio State University 2009 Dissertation Committee: Approved by Professor Ching-Shih Chen, Advisor Professor Pui-Kai (Tom) Li Adviser Professor Werner Tjarks Pharmacy Gradate Program Professor Dale Hoyt COPYRIGHT BY JIAN YANG 2009 ABSTRACT As of 2008, prostate cancer remains the number one cause of estimated new cancer cases in American men. Although early prostate cancer responds to androgen ablation, most tumors eventually recur as hormone-refractory prostate cancer (HRPC). Recent advances have identified many abnormal signaling pathways that contribute to the development of HRPC, mainly including dysregulation of androgen receptor (AR) function and the over- expression of the anti-apoptotic proteins, Bcl-2/Bcl-xL. It was found that thiazolidinediones (TZD), which include the anti-diabetic agents troglitazone, rosiglitazone, pioglitazone and ciglitazone, possess anti-tumor activity. It has been revealed that the anti-tumor activity of the TZDs could be attributed to PPARγ- independent mechanisms including Bcl-2/Bcl-xL inhibition and AR transcriptional repression. The objective of this dissertation is to further modify the TZD structures to enhance anti-prostate cancer activity by targeting the dysregulated Bcl-2/Bcl-xL and AR signaling pathways. Directed by method of molecular modeling, over 50 troglitazone derivatives have been designed and synthesized in two stages, yielding the optimal compound HepCNCF3, which showed two orders of magnitude improvement in Bcl-xL/Bcl-2 inhibition ii compared to troglitazone. Results from molecular modeling, Western blotting assay and co-immunoprecipitation assay confirmed the inhibitory effects of HepCNCF3 on Bcl- 2/Bcl-xL and its function of apoptosis induction at low micromolar level in prostate cancer cells. The effects of ciglitazone on transcriptional repression of AR have been verified, and as a lead compound, ciglitazone possessed advantages of simpler molecular and stronger potency compared to troglitazone. Partly aided by method of focused-library solid-phase combinatorial chemistry, three stages of optimization have been performed based on ciglitazone. Out of totally approximately 150 new derivatives, the optimal compounds such as CG12, CC5 and CC22 showed one order of magnitude improvement in AR repression and cytotoxicity in LNCaP cells than ciglitazone. The optimized activites of these compounds have been confirmed in AR reporter gene luciferase assay, Western blotting assay and flow-cytometry analysis. Overall, through comprehensive methods of computer-based design, ligand-based design and solid-phase combinatorial chemistry, several promising agents targeting on the abnormalities in prostate cancer, particularly in HRPC, have been successfully developed and their effects of Bcl-2/Bcl-xL inhibition or AR ablation have been validated. iii Dedicated to my grandparents, my parents, and especially my wife Yanhui and my daughter Alisa iv ACKNOWLEDGEMENTS I would like to give special thanks to my advisor, Dr. Ching-shih Chen for his guidance, encouragement, support and patience. I could never finish my Ph.D training without his consistent kind help. I would also like to express my sincere appreciation for the faculty in college of pharmacy, especially Dr. Pui-Kai (Tom) Li, Dr. Werner Tjarks, Dr. Dale Hoyt, Dr. Kenneth Chan and Dr. Duxin Sun for all their help and advice. I am grateful to Dr. Da-sheng Wang for his advices in chemistry and Dr. Samuel Kulp for his assistance with animal studies and proofreading. I would like to thank Wei (Dennis) Shuo, Dr. Hao-Chieh(Jay) Chiu, Errica and other labmates in helping biological evaluation. I would like to thank Hsiao-Ching Yang and Su-Lin (Jack) Lee in helping molecular modeling. I would like thank Ms Judith Gallucci for analyzing the crystal structure and providing the experimental details. I want to thank Dr. Pui-Kai (Tom) Li, Ms Kathy Brooks, Ms Beth Bucher and other staff in my gradate program, office of international affairs and the graduate school for their support to make my graduate studies going smoothly. I would like give thanks to all the members in Dr. Chen’s lab and all my friends including Ye’s family, Yunlong’s family, Mathew, Xiaobing’s family, Mingxuan’s family, Dennis’ family and so on during my Ph.D study. Particularly, I would like present many thanks to my wife, Yanhui Lu, my daughter, Alisa Yang, my parents and my parents-in-law. v VITA 1994-1998……………………………………………….. B.S., Medicinal Chemistry College of Pharmacy, Beijing Medical University, Beijing, China 1998-2000………………. Professional Teacher Assistant and Research Assistant College of Pharmacy, Beijing Medical University, Beijing, China 2000-2003………………………………………………. M.S., Medicinal Chemistry College of Pharmacy, Peking University, Beijing, China 2003-2004……………………………………………………………. Group Leader Haimen Wisdom Pharmaceutical Co., Haimen, Jiangsu, China 2004-present……………. Ph.D. Candidate, Medicinal Chemistry & Pharmacognosy The Ohio State University, Columbus, OH, USA PUBLICATIONS 1. PPARγ-Independent Antitumor Effects of Thiazolidinediones. Shuo Wei, Jian Yang, Su-Lin Lee, Samuel K. Kulp, and Ching-Shih Chen. Cancer Letters (2009) Cancer Letters 276, 119–124. 2. Pharmacological Exploitation of the PPARγ Agonist Ciglitazone to Develop a Novel Class of Androgen Receptor-Ablative Agents Jian Yang, Shuo Wei, Dasheng Wang, Yu-Chieh Wang, Samuel K. Kulp, and Ching-Shih Chen. Journal of Medicinal Chemistry (2008) 51, 2100–2107. 3. A Novel Mechanism by Which Thiazolidinediones Facilitate the Proteasomal Degradation of Cyclin D1 in Cancer Cells. Shuo Wei, Hsiao-Ching Yang, Hsiao- Ching Chuang, Jian Yang, Samuel K. Kulp, Pei-Jung Lu, Ming-Derg Lai, and Ching-Shih Chen. Journal of Biological Chemistry (2008) 283, 26759-70. 4. Bioassay-directed Purification of an Acidic Phospholipase A2 from Agkistrodon halys pallas Venom. Yuwei Wang, Guohui Cui, Ming Zhao, Jian Yang, Chao Wang, Roger W. Giese, and Shiqi Peng. Toxicon (2008) 51, 1131–1139. 5. Development of Small-Molecule Cyclin D1-Ablative Agents. Jui-Wen Huang, Chung-Wai Shiau, Jian Yang, Dasheng Wang, Hao-Chieh Chiu, Ching-Yu Chen, and Ching-Shih Chen. Journal of Medicinal Chemistry (2006) 49, 4684-4689. 6. Synthesis and Evaluations of Pentahydroxylhexyl-L-Cysteine and Its Dimer as Chelating Agents for Cadmium or Lead Decorporation. Chao Wang, Ming Zhao, Jian vi Yang, Xingwei Li, and Shiqi Peng. Toxicology and Applied Pharmacology (2004) 200, 229-236. 7. Identification, Synthesis and Bioassay for the Metabolites of P6A. Ming Zhao, Chao Wang, Jian Yang, Jiangyuan Liu, Youxuan Xu, Yanfen Wu and Shiqi Peng. Bioorganic & Medicinal Chemistry (2003) 11, 4913-4920. 8. Studies on the Synthesis of Estrogen-GHRPS. Chao Wang, Ming Zhao, Weina Cui, Jian Yang, and Shiqi Peng. Synthetic Communication (2003) 33, 1633-1641. 9. Studies on the Synthesis and Anti-osteoporosis of Estrogen-GHRPs Linkers. Chao Wang, Weina Cui, Ming Zhao, Jian Yang, and Shiqi Peng. Bioorganic and Medicinal Chemistry Letters (2003) 13, 143-146. 10. Synthesis and Analgesic Effects of Kyotorphin - Steroid Linkers. Chao Wang, Ming Zhao, Jian Yang, and Shiqi Peng. Steroids (2001) 66, 811-815. 11. Synthesis of RGD-Containing Peptides and Their Vasodilation Effect. Ming Zhao, Chao Wang, Jian Yang, and Shiqi Peng. Preparative Biochemistry & Biotechnology (2000) 30, 247-256. 12. The Establishment of a Rat Model of Thrombolysis and Its Application. Na Lin, Jian Yang, Chao Wang, Ming Zhao, and Shiqi Peng. Journal of Beijing Medical University (2000) 32, 283-284. 13. Androgen Receptor-Ablative Agents. Ching-Shih Chen, Dasheng Wang, Jian Yang. United States Provisional Patent, Serial No. 61/030,860; filed on February 22, 2008. 14. Imidazoline Substituted Phenyloxyacetyl Oligopeptide Compounds: Their Synthesis and Applications in Medicine. Shiqi Peng, Ming Zhao, Chao Wang, Junling Liu, Jian Yang. Chinese Patent, Application No. 02134992.4, 2003. 15. Imidazoline Substituted Phenyloxyacetyl Oligopeptide Derivatives: Their Synthesis and Applications in Medicine. Shiqi Peng, Ming Zhao, Chao Wang, Junling Liu, Jian Yang. Chinese Patent, Application No. 02134994.0, 2003. FIELDS OF STUDY Major Field: Pharmacy Specification: Medicinal Chemistry vii TABLE OF CONTENTS Page Abstract……………………………………………………………………………………ii Dedication..……………………………………………………………………………….iv Acknowledgements………………………………………………………………..………v Vita………………………………………………………………………………………..vi List of tables………………………………………………………………………………xi List of figures……………………………………………………………………………xiv Chapters: 1. Introduction………………………………………………………………………..……1 1.1 Prostate cancer, current treatments and agents in development…………….………1 1.2 Mechanisms of castration resistant prostate cancer (CRPC) …………..…………...5 1.3 AR as a good target for treatment in CRPC……………………………………..…..7 1.4 Anti-apopotic proteins Bcl-2/Bcl-xL as targets for treatment of CRPC……….……9 1.5 Thiazolidinediones, mechanisms in anti-cancer and structure optimization………13 2. Development of troglitazone derivatives targeting on Bcl-2/Bcl-xL directed by molecular modeling…………………………………………………………………...…17 2.1 Design of ∆2TG derivatives directed by molecular modeling ……………………17 2.2 ∆2TG derivatives with an n-alkyl side chain …………………………………...…21 2.3 ∆2TG
Load more

Recommended publications
  • Stimulatory Action of Telmisartan, an Antagonist of Angiotensin II Receptor, on Voltage-Gated Na+ Current: Experimental and Theoretical Studies
    Chinese Journal of Physiology 61(1): 1-13, 2018 1 DOI: 10.4077/CJP.2018.BAG516 Stimulatory Action of Telmisartan, an Antagonist of Angiotensin II Receptor, on Voltage-Gated Na+ Current: Experimental and Theoretical Studies Tzu-Tung Chang, Chia-Jung Yang, Yu-Chi Lee, and Sheng-Nan Wu Department of Physiology, National Cheng Kung University Medical College, Tainan 70101, Taiwan, Republic of China Abstract Telmisartan (Tel) is recognized as a non-peptide blocker of AT1R. Whether this agent has any direct effects on ion currents remains unexplored. In whole-cell current recordings, addition of Tel + increased the peak amplitude of voltage-gated Na (NaV) current (INa) accompanied by the increased time constant of INa inactivation in differentiated NSC-34 motor neuron-like cells. Tel-stimulated INa in these cells is unlinked to either blockade of AT1R or activation of peroxisome proliferator-activated receptor gamma (PPAR-γ). In order to explore how this compound affects the amplitude and kinetics of INa in neurons, a Hodgkin-Huxley-based (HH-based) model designed to mimic effect of Tel on the functional activities of neurons was computationally created in this study. In this framework, the parameter for h inactivation gating variable, which was changed in a stepwise fashion, was implemented + + to predict changes in membrane potentials (V) as a function of maximal Na (GNa), K conductance (GK), or both. As inactivation time course of INa was increased, the bifurcation point of V versus GNa became lower, and the range between subcritical and supercritical values at the bifurcation of V versus GK correspondingly became larger.
    [Show full text]
  • REVIEW Peroxisome Proliferator-Activated Receptors In
    199 REVIEW Peroxisome proliferator-activated receptors in reproductive tissues: from gametogenesis to parturition P Froment, F Gizard1, D Defever2, B Staels1, J Dupont3 and P Monget3 INSERM U.418, UMR Communications Cellulaire et Différenciation, Hôpital Debrousse, 29 rue Soeur Bouvier, 69322 Lyon, France 1INSERM U.545, Institut Pasteur de Lille et Faculté de Pharmacie Université de Lille 2, 1 rue du Pr Calmette, 59019 Lille, France 2LMCB, Department of Molecular Biomedical Research, V.I.B., Technologiepark 927, B-9052 Ghent (Zwijnaarde), Belgium 3Physiologie de la reproduction et des comportements, UMR 6175 INRA-CNRS-Université F. Rabelais de Tours-Haras Nationaux, 37380 Nouzilly, France (Requests for offprints should be addressed to P Froment; [email protected]) Abstract Peroxisome proliferator-activated receptors (PPAR, granulosa cell proliferation and steroidogenesis in vitro. All PPAR/ and PPAR) are a family of nuclear receptors these recent data raise new questions about the biologic that are activated by binding of natural ligands, such as actions of PPARs in reproduction and their use in polyunsaturated fatty acids or by synthetic ligands. Syn- therapeutic treatments of fertility troubles such as PCOS thetic molecules of the glitazone family, which bind to or endometriosis. In this review, we first describe the roles PPAR, are currently used to treat type II diabetes and of PPARs in different compartments of the reproductive also to attenuate the secondary clinical symptoms fre- axis (from male and female gametogenesis to parturition), quently associated with insulin resistance, including poly- with a focus on PPAR. Secondly, we discuss the possible cystic ovary syndrome (PCOS). PPARs are expressed molecular mechanisms underlying the effect of glitazones in different compartments of the reproductive system on PCOS.
    [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]
  • PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1
    Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 2 Table 1. This table enumerates products described by International Non-proprietary Names INN which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service CAS registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known.
    [Show full text]
  • 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.
    [Show full text]
  • Modifications to the Harmonized Tariff Schedule of the United States To
    U.S. International Trade Commission COMMISSIONERS Shara L. Aranoff, Chairman Daniel R. Pearson, Vice Chairman Deanna Tanner Okun Charlotte R. Lane Irving A. Williamson Dean A. Pinkert Address all communications to Secretary to the Commission United States International Trade Commission Washington, DC 20436 U.S. International Trade Commission Washington, DC 20436 www.usitc.gov Modifications to the Harmonized Tariff Schedule of the United States to Implement the Dominican Republic- Central America-United States Free Trade Agreement With Respect to Costa Rica Publication 4038 December 2008 (This page is intentionally blank) Pursuant to the letter of request from the United States Trade Representative of December 18, 2008, set forth in the Appendix hereto, and pursuant to section 1207(a) of the Omnibus Trade and Competitiveness Act, the Commission is publishing the following modifications to the Harmonized Tariff Schedule of the United States (HTS) to implement the Dominican Republic- Central America-United States Free Trade Agreement, as approved in the Dominican Republic-Central America- United States Free Trade Agreement Implementation Act, with respect to Costa Rica. (This page is intentionally blank) Annex I Effective with respect to goods that are entered, or withdrawn from warehouse for consumption, on or after January 1, 2009, the Harmonized Tariff Schedule of the United States (HTS) is modified as provided herein, with bracketed matter included to assist in the understanding of proclaimed modifications. The following supersedes matter now in the HTS. (1). General note 4 is modified as follows: (a). by deleting from subdivision (a) the following country from the enumeration of independent beneficiary developing countries: Costa Rica (b).
    [Show full text]
  • Comparative Safety and Effectiveness of Type 2 Diabetes Medicines Final Report September 2014
    Type 2 Diabetes review – ToR 4 COMPARATIVE SAFETY AND EFFECTIVENESS OF TYPE 2 DIABETES MEDICINES FINAL REPORT SEPTEMBER 2014 A report by the Centre for Applied Health Economics (CAHE), Griffith University Type 2 Diabetes review – ToR 4 This report was commissioned by the Pharmaceutical Evaluation Branch, Department of Health, the Australian Government. Researchers: Erika Turkstra Senior research fellow, health technology assessment Martin Downes Research fellow, health technology assessment Emilie Bettington Senior research assistant Tracy Comans Senior research fellow, health technology assessment Paul Scuffham Professor and chair in health economics The assistance of Sanjeewa Kularatna with the data extraction and Gabor Mihala with the statistical analyses is appreciated. The advice provided by the Post-Market Review Section, Pharmaceutical Evaluation Branch, Department of Health and the Reference Group is also appreciated. Type 2 Diabetes review – ToR 4 CONTENTS ACRONYMS ............................................................................................................. III EXECUTIVE SUMMARY ............................................................................................ 1 PURPOSE OF THE REVIEW ........................................................................................... 1 BACKGROUND ............................................................................................................ 1 REVIEW OF CLINICAL GUIDELINES ...............................................................................
    [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]
  • Pharmaceuticals Appendix
    )&f1y3X PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE )&f1y3X PHARMACEUTICAL APPENDIX TO THE TARIFF SCHEDULE 3 Table 1. This table enumerates products described by International Non-proprietary Names (INN) which shall be entered free of duty under general note 13 to the tariff schedule. The Chemical Abstracts Service (CAS) registry numbers also set forth in this table are included to assist in the identification of the products concerned. For purposes of the tariff schedule, any references to a product enumerated in this table includes such product by whatever name known. Product CAS No. Product CAS No. ABAMECTIN 65195-55-3 ADAPALENE 106685-40-9 ABANOQUIL 90402-40-7 ADAPROLOL 101479-70-3 ABECARNIL 111841-85-1 ADEMETIONINE 17176-17-9 ABLUKAST 96566-25-5 ADENOSINE PHOSPHATE 61-19-8 ABUNIDAZOLE 91017-58-2 ADIBENDAN 100510-33-6 ACADESINE 2627-69-2 ADICILLIN 525-94-0 ACAMPROSATE 77337-76-9 ADIMOLOL 78459-19-5 ACAPRAZINE 55485-20-6 ADINAZOLAM 37115-32-5 ACARBOSE 56180-94-0 ADIPHENINE 64-95-9 ACEBROCHOL 514-50-1 ADIPIODONE 606-17-7 ACEBURIC ACID 26976-72-7 ADITEREN 56066-19-4 ACEBUTOLOL 37517-30-9 ADITOPRIME 56066-63-8 ACECAINIDE 32795-44-1 ADOSOPINE 88124-26-9 ACECARBROMAL 77-66-7 ADOZELESIN 110314-48-2 ACECLIDINE 827-61-2 ADRAFINIL 63547-13-7 ACECLOFENAC 89796-99-6 ADRENALONE 99-45-6 ACEDAPSONE 77-46-3 AFALANINE 2901-75-9 ACEDIASULFONE SODIUM 127-60-6 AFLOQUALONE 56287-74-2 ACEDOBEN 556-08-1 AFUROLOL 65776-67-2 ACEFLURANOL 80595-73-9 AGANODINE 86696-87-9 ACEFURTIAMINE 10072-48-7 AKLOMIDE 3011-89-0 ACEFYLLINE CLOFIBROL 70788-27-1
    [Show full text]
  • Pharmaceuticals Compositions Comprising Sulphonylurea-Class Insulin Secretagogue and Polyethylene Glycol Castor Oil
    (19) & (11) EP 2 438 911 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 11.04.2012 Bulletin 2012/15 A61K 9/20 (2006.01) A61K 31/4439 (2006.01) A61K 31/64 (2006.01) A61K 9/16 (2006.01) (21) Application number: 10013440.2 (22) Date of filing: 08.10.2010 (84) Designated Contracting States: (72) Inventor: The designation of the inventor has not AL AT BE BG CH CY CZ DE DK EE ES FI FR GB yet been filed GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO PL PT RO RS SE SI SK SM TR (74) Representative: Hodzar, Damjan et al Designated Extension States: Lek Pharmaceuticals d.d. BA ME Verovskova 57 1526 Ljubljana (SI) (71) Applicant: LEK Pharmaceuticals d.d. 1526 Ljubljana (SI) (54) Pharmaceuticals compositions comprising sulphonylurea-class insulin secretagogue and polyethylene glycol castor oil (57) The present invention relates to the field of a rea-class insulin secretagogue active pharmaceutical in- pharmaceutical technology. More specifically, the gredient and at the same time, when both formulated into present invention relates to a pharmaceutical composi- a pharmaceutical composition, ensures satisfying or ex- tion comprising sulphonylurea-class insulin secreta- ceeding other parameters like for example stability, hard- gogue and a surface active agent. Surface active agent ness, friability and handling of said pharmaceutical com- obtainable by reacting castor oil or hydrogenated castor position. oil with ethylene oxide, preferably hydrogenated castor oil, substantially improves dissolution of the sulphonylu- EP 2 438 911 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 438 911 A1 Description Field of the invention 5 [0001] The present invention relates to the field of a pharmaceutical technology.
    [Show full text]
  • Curriculum Vitae
    David C. Klonoff MD, FACP, FRCP (Edin), Fellow AIMBE Page 1 CURRICULUM VITAE DAVID CHARLES KLONOFF, M.D., FACP, FRCP (Edin), FELLOW AIMBE Medical Director, Diabetes Research Institute, Mills-Peninsula Medical Center 100 South San Mateo Drive, Room 5147, San Mateo, California 94401 Phone 650-696-4260 / Fax 650-696-4269 [email protected] SUMMARY David C. Klonoff, M.D. is an endocrinologist specializing in the development and use of diabetes technology. He is Medical Director of the Dorothy L. and James E. Frank Diabetes Research Institute of Mills-Peninsula Medical Center in San Mateo, California and a Clinical Professor of Medicine at UCSF. Dr. Klonoff received the American Diabetes Association’s 2019 Outstanding Physician Clinician Award. He received an FDA Director’s Special Citation Award in 2010 for outstanding contributions related to diabetes technology. In 2012 Dr. Klonoff was elected as a Fellow of the American Institute of Medical and Biological Engineering (AIMBE) and cited as among the top 2% of the world’s bioengineers for his engineering work in diabetes technology. He received the 2012 Gold Medal Oration and Distinguished Scientist Award from the Dr. Mohan’s Diabetes Specialities Centre and Madras Diabetes Research Foundation of Chennai, India. Dr. Klonoff was invited to speak to the US Congressional Diabetes Caucus in 2017, participate in the White House Health and Cybersecurity Roundtable in 2015, and speak at the European Parliament in 2010. He is the Founding Editor- in-Chief of Journal of Diabetes Science and Technology. He has authored over 270 publications in PubMed journals including four of the first ten articles on diabetes device cybersecurity.
    [Show full text]
  • Open Full Page
    1288 Vol. 8, 1288–1294, May 2002 Clinical Cancer Research Nuclear Receptor Agonists As Potential Differentiation Therapy Agents for Human Osteosarcoma1 Rex C. Haydon,2 Lan Zhou,2 Tao Feng, Conclusions: Our findings suggest that PPAR␥ and/or Benjamin Breyer, Hongwei Cheng, Wei Jiang, RXR ligands may be used as efficacious adjuvant therapeu- tic agents for primary osteosarcoma, as well as potential Akira Ishikawa, Terrance Peabody, chemopreventive agents for preventing the recurrence and Anthony Montag, Michael A. Simon, and metastasis of osteosarcoma after the surgical removal of the Tong-Chuan He3 primary tumors. Molecular Oncology Laboratory, Department of Surgery, The University of Chicago Medical Center, Chicago, Illinois 60637 INTRODUCTION Osteosarcoma is the most common primary malignant tu- mor of bone, encompassing a class of osteoid-producing neo- ABSTRACT plasms that range in clinical behavior and responsiveness to Purpose: This study was designed to investigate therapeutic regimens (1, 2). Best known of these lesions, the whether nuclear receptor agonists can be used as potential classic high-grade osteosarcoma primarily afflicts individuals in differentiation therapy agents for human osteosarcoma. the second decade of life and is distinguished by its locally Experimental Design: Four osteosarcoma cell lines aggressive character and early metastatic potential. Metastatic (143B, MNNG/HOS, MG-63, and TE-85) were treated with disease is often not apparent at diagnosis and causes the over- proliferator-activated receptor (PPAR)␥ agonists, troglita- whelming majority of deaths among patients with this disease. zone and ciglitazone, and a retinoid X receptor (RXR) li- Recurrent or metastatic tumors are significantly less sensitive, if gand, 9-cis retinoic acid.
    [Show full text]