DOCSLIB.ORG

Us 2018 / 0296525 A1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

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 . g . , formation of lipid - rich deposits , oxidative stress , local A61K 38 / 18 ( 2006 . 01 ) inflammation , cell death and neovascularization ) are used to A61K 39 /395 ( 2006 .01 ) treat or slow the progression of atrophic AMD ( including ( 52 ) U . S . CI. non - central GA and central GA ) or neovascular AMD ( in CPC . .. .. .. .. A61K 31/ 366 ( 2013 .01 ) ; A61P 27 / 02 cluding types 1 , 2 and 3 NV ) , and / or to prevent or delay the ( 2018 .01 ) ; A61K 9 /0048 ( 2013 .01 ) ; A61K onset of AMD , advanced AMD and /or neovascular AMD . 39 /3955 ( 2013 .01 ) ; A61K 45 / 06 ( 2013 .01 ) ; Specification includes a Sequence Listing . Patent Application Publication Oct . 18 , 2018 Sheet 1 of 4 US 2018 /0296525 A1 EXT Subretinaldrusenoid deposit X 044 * * * . 1 . I . II IT . ! ! . WW . # # T . SA * * . .. -8200.000300 ! . ! ! 29 . www * * ! . BaselmoundoIS 288 FIG.1 WE LA BESSON BlindPre- 6003556 Qw878 $ MINIMURNucleus 700 MIUIUSIONDABAVITVAMOM19-3dd 0 W Patent Application Publication Oct. 18 , 2018 Sheet 2 of 4 US 2018 /0296525 A1 oil Red O Staining -56 % (p = 0. 007 ) p = 0 .84 ORO-score UNTY teretettet OOOOOOOOOOOOOOOOOOOOOOOOOOoodbodoodoodooDOO Injected Eyes neviririririnig Non -injected ??????????????????????? Eyes eccete Tiiiiii Treatment Group (L - 4F ) ControlGroup ( SL - 4F /Placebo ) FIG . 2 Patent Application Publication Oct . 18 , 2018 Sheet 3 of 4 US 2018 /0296525 A1 Filipin Staining FluorescenceIntensity (ArbitraryUnits,Mean4-SE) -68 % * p = 0 .037 many injected Eyes Non -Injected Injected Eyes Non - injected Eyes Treatment Group ( L -4F ) Control Group ( SL - 4F1Placebo ) FIG . 3 MAC ( c5b9 ) Staining -58 % * p < 0 .0016 p < 0 . 31 viiiiiiiiiii una FluorescenceIntensity(ArbitraryUnits+1-SE) kutukutukutukutukutukutukutukutukutukutukutu kutukutukutukutukutukutukutukutukutukutukutukutuku OOOOO OOOOOOOOOOOOOOOOOOOOOOOOOO injected Eyes Non - injected Injected Eyes Non -injected mmmmmmmmmmmmmmmmmmmmmmmmmm eyes Treatment Group (L -4F ) Control Group ( SL - 4F /Placebo ) FIG . 4 Patent Application Publication Oct . 18 , 2018 Sheet 4 of 4 US 2018 /0296525 A1 Complement Activator Factor D Staining iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii i iiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiiii . ???????????????????????????????????? FluorescenceIntensity (ArbitraryUnits,Mean*-SE) 0 ~ 690 Die personale 0000000000000000000000000 Injected Eyes Non -injected Injected Eyes Non -injected Eyes Eyes Treatment Group (L -4F ) Control Group (L -4F / Placebo ) FIGR . 5 Bruch ' s Membrane Thickness in TEM - 24 % # p = 0 .0118 Bruch'sThickness(Mean+SE,um) ????????????????????????? Injected Eyes Non - injected Non - injected Eyes Eyes 10000000000000000000000000000000000000000000000000000000000000000000000 Treatment Group ( L -4F ) ControlGroup ( SL - 4F / Placebo ) FIG . 6 US 2018 /0296525 A1 Oct . 18 , 2018 TREATMENT OF AGE - RELATED MACULAR 0004 ] The one or more therapeutic agents that can be DEGENERATION AND OTHER EYE used to treat AMD and other eye diseases and disorders DISEASES WITH ONE OR MORE include without limitation : THERAPEUTIC AGENTS [0005 ] 1 ) anti- dyslipidemic agents ; [ 0006 ] 2 ) PPAR - a agonists , PPAR - d agonists and PPAR - Y RELATED APPLICATIONS agonists ; [ 0007 ] 3 ) anti - amyloid agents and inhibitors of other toxic [0001 ] This application claims priority to and the benefit substances ( e . g . , aldehydes ) ; of U . S . Provisional Patent Application No . 62 /467 ,073 filed [0008 ] 4 ) inhibitors of lipofuscin or components thereof; on Mar. 3 , 2017 , which is incorporated herein by reference [ 0009 ] 5 ) visual /light cycle modulators and dark adapta in its entirety for all purposes . tion agents; [0010 ] 6 ) antioxidants ; BACKGROUND OF THE DISCLOSURE [0011 ] 7 ) neuroprotectors (neuroprotectants ) ; [0002 ] Age -related macular degeneration ( AMD ) affects [0012 ] 8 ) apoptosis inhibitors and necrosis inhibitors ; about 14 - 24 % of the people aged 65 to 74 and about 35 % of [0013 ] 9 ) C - reactive protein inhibitors ; the people over 75 , and about 200 million people , around the [0014 ] 10 ) inhibitors of the complement system or com world , and is the leading cause of legal blindness in devel ponents ( e . g ., proteins) thereof; oped countries . AMD results in vision impairment or loss in [ 0015 ] 11 ) inhibitors of inflammasomes ; the center of the visual field ( the macula ) because of damage [ 0016 ] 12 ) anti - inflammatory agents ; to the retina . The two principal forms of AMD are atrophic 0017 ] 13 ) immunosuppressants ; ( non - exudative or " dry ” ) AMD and neovascular ( exudative [ 0018 ] 14 ) modulators ( inhibitors and activators ) of matrix or " wet " ) AMD . Atrophic AMD is characterized by geo metalloproteinases and other inhibitors of cell migration ; graphic atrophy (GA ) at the center of the macula in the [0019 ] 15 ) anti -angiogenic agents ; advanced stage of AMD , and vision can slowly deteriorate [0020 ] 16 ) laser therapies , photodynamic therapies and over many years due to loss of photoreceptors and devel radiation therapies; opment ofGA . Neovascular AMD is a more severe form of [ 0021] 17 ) agents that preserve or improve the health of AMD and is characterized by neovascularization ( e . g . , chor the endothelium and / or the blood flow of the vascular oidal neovascularization in the advanced stage of AMD , system of the eye ; and which can rapidly lead to blindness . Neovascular AMD f 0022 ] 18 ) cell ( e . g ., RPE cell ) replacement therapies . affects about 30 million patients worldwide and is a leading [0023 ] In some embodiments , an anti -dyslipidemic agent cause of vision loss in people aged 60 years or older if ( e . g . , an apo mimetic such as an apoA - I mimetic and /or an untreated , patients are likely to lose central vision in the apoE mimetic , and / or a statin ) is used in conjunction with an affected eye within 24 months of disease onset. About 85 % antioxidant, an anti - inflammatory agent, a complement of AMD patients have the dry form , and about 15 % develop inhibitor , a neuroprotector or an anti - angiogenic agent, or neovascular AMD . There is no approved treatment for any combination or all thereof, to treat or slow the progres atrophic AMD in the United States , while approved treat sion of atrophic AMD ( including central and non - central ments for neovascular AMD (primarily anti- angiogenic geographic atrophy ) and /or neovascular AMD ( including agents ) show efficacy in about 50 % of neovascular AMD types 1 , 2 and 3 neovascularization ) , and / or to prevent or patients . delay the onset of atrophic AMD or neovascular AMD . [0024 . Besides AMD , other eye diseases and disorders SUMMARY OF THE DISCLOSURE that can be treated with one or more therapeutic agents [0003 ] The present disclosure provides for the treatment of described herein include without limitation maculopathy AMD and other eye diseases and disorders using one or ( e . g ., age - related maculopathy and diabetic maculopathy ) , more therapeutic agents . In certain embodiments , the one or macular edema ( e . g . , diabetic macular edema [DME ) and more therapeutic agents include an anti - dyslipidemic agent, macular edema following retinal vein occlusion ( RVO ]) , such as an apolipoprotein ( apo ) mimetic ( e . g ., an apoA - I retinopathy ( e . g . , diabetic retinopathy [ including in patients mimetic such as L - 4F or D -4F , and / or an apoE mimetic such with DME ]) , RVO ( e . g . , central RVO and branch RVO ) , as AEM - 28 - 14 ) and /or a statin ( e . g . , atorvastatin and /or Coats ' disease ( exudative retinitis ) , uveitis , retinal pigment simvastatin ) . The one or more therapeutic
Recommended publications
  • Chemicals in the Fourth Report and Updated Tables Pdf Icon[PDF

    Chemicals in the Fourth Report and Updated Tables Pdf Icon[PDF

    Chemicals in the Fourth National Report on Human Exposure to Environmental Chemicals: Updated Tables, March 2021 CDC’s Fourth National Report on Human Exposure to Environmental Chemicals: Updated Tables, March 2021 provides exposure data on the following chemicals or classes of chemicals. The Updated Tables contain cumulative data from national samples collected beginning in 1999–2000 and as recently as 2015-2016. Not all chemicals were measured in each national sample. The data tables are available at https://www.cdc.gov/exposurereport. An asterisk (*) indicates the chemical has been added since publication of the Fourth National Report on Human Exposure to Environmental Chemicals in 2009. Adducts of Hemoglobin Acrylamide Formaldehyde* Glycidamide Tobacco Alkaloids and Metabolites Anabasine* Anatabine* Cotinine Cotinine-n-oxide* Hydroxycotinine* Trans-3’-hydroxycotinine* 1-(3-Pyridyl)-1-butanol-4-carboxylic acid* Nicotine* Nicotine-N’-oxide* Nornicotine* Tobacco-Specific Nitrosamines (TSNAs) N’-Nitrosoanabasine (NAB)* N’-Nitrosoanatabine (NAT)* N’-Nitrosonornicotine (NNN)* Total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol) (NNAL)* Volatile N-nitrosamines (VNAs) N-Nitrosodiethylamine (NDEA)* N-Nitrosoethylmethylamine (NMEA)* N-Nitrosomorpholine (NMOR)* N-Nitrosopiperidine (NPIP)* N-Nitrosopyrrolidine (NPYR)* Disinfection By-Products Bromodichloromethane Dibromochloromethane Tribromomethane (Bromoform) Trichloromethane (Chloroform) Personal Care and Consumer Product Chemicals and Metabolites Benzophenone-3 Bisphenol A Bisphenol F* Bisphenol
  • DRAFT Indicators Biomonitoring: Perfluorochemicals (Pfcs)

    DRAFT Indicators Biomonitoring: Perfluorochemicals (Pfcs)

    America’s Children and the Environment, Third Edition DRAFT Indicators Biomonitoring: Perfluorochemicals (PFCs) EPA is preparing the third edition of America’s Children and the Environment (ACE3), following the previous editions published in December 2000 and February 2003. ACE is EPA’s compilation of children’s environmental health indicators and related information, drawing on the best national data sources available for characterizing important aspects of the relationship between environmental contaminants and children’s health. ACE includes four sections: Environments and Contaminants, Biomonitoring, Health, and Special Features. EPA has prepared draft indicator documents for ACE3 representing 23 children's environmental health topics and presenting a total of 42 proposed children's environmental health indicators. This document presents the draft text, indicator, and documentation for the PFCs topic in the Biomonitoring section. THIS INFORMATION IS DISTRIBUTED SOLELY FOR THE PURPOSE OF PRE- DISSEMINATION PEER REVIEW UNDER APPLICABLE INFORMATION QUALITY GUIDELINES. IT HAS NOT BEEN FORMALLY DISSEMINATED BY EPA. IT DOES NOT REPRESENT AND SHOULD NOT BE CONSTRUED TO REPRESENT ANY AGENCY DETERMINATION OR POLICY. For more information on America’s Children and the Environment, please visit www.epa.gov/ace. For instructions on how to submit comments on the draft ACE3 indicators, please visit www.epa.gov/ace/ace3drafts/. March 2011 DRAFT: DO NOT QUOTE OR CITE Biomonitoring: Perfluorochemicals 1 Perfluorochemicals (PFCs) 2 3 Perfluorochemicals (PFCs) are a group of manmade chemicals that have been used since the 4 1950s in many consumer products.1 The structure of these chemicals makes them very stable, 5 hydrophobic (water-repelling), and oleophobic (oil-repelling).
  • And Polyfluoroalkyl Substances – Chemical Variation and Applicability of Current Fate Models

    And Polyfluoroalkyl Substances – Chemical Variation and Applicability of Current Fate Models

    CSIRO PUBLISHING Environ. Chem. 2020, 17, 498–508 Research Paper https://doi.org/10.1071/EN19296 Investigating the OECD database of per- and polyfluoroalkyl substances – chemical variation and applicability of current fate models Ioana C. Chelcea,A Lutz Ahrens,B Stefan O¨ rn,C Daniel MucsD and Patrik L. Andersson A,E ADepartment of Chemistry, Umea˚ University, SE-901 87 Umea˚, Sweden. BDepartment of Aquatic Sciences and Assessment, Swedish University of Agricultural Sciences (SLU), Box 7050, SE-750 07 Uppsala, Sweden. CDepartment of Biomedical Sciences and Veterinary Public Health, Swedish University of Agricultural Sciences (SLU), SE-750 07 Uppsala, Sweden. DRISE SP – Chemical and Pharmaceutical Safety, Forskargatan 20, 151 36 So¨derta¨lje, Sweden. ECorresponding author. Email: [email protected] Environmental context. A diverse range of materials contain organofluorine chemicals, some of which are hazardous and widely distributed in the environment. We investigated an inventory of over 4700 organofluorine compounds, characterised their chemical diversity and selected representatives for future testing to fill knowledge gaps about their environmental fate and effects. Fate and property models were examined and concluded to be valid for only a fraction of studied organofluorines. Abstract. Many per- and polyfluoroalkyl substances (PFASs) have been identified in the environment, and some have been shown to be extremely persistent and even toxic, thus raising concerns about their effects on human health and the environment. Despite this, little is known about most PFASs. In this study, the comprehensive database of over 4700 PFAS entries recently compiled by the OECD was curated and the chemical variation was analysed in detail.
  • 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

    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.
  • Cross-Sectional Study of the Association Between Serum Perfluorinated Alkyl Acid Concentrations and Dental Caries Among US Adolescents (NHANES 1999–2012)

    Cross-Sectional Study of the Association Between Serum Perfluorinated Alkyl Acid Concentrations and Dental Caries Among US Adolescents (NHANES 1999–2012)

    Open access Research BMJ Open: first published as 10.1136/bmjopen-2018-024189 on 5 February 2019. Downloaded from Cross-sectional study of the association between serum perfluorinated alkyl acid concentrations and dental caries among US adolescents (NHANES 1999–2012) Nithya Puttige Ramesh,1 Manish Arora,2 Joseph M Braun1 To cite: Puttige Ramesh N, ABSTRACT Strengths and limitations of this study Arora M, Braun JM. Cross- Study objectives Perfluoroalkyl acids (PFAAs) are a class sectional study of the of anthropogenic and persistent compounds that may ► Our study contributes to a gap in the literature by association between serum impact some biological pathways related to oral health. perfluorinated alkyl acid examining the relationship between perfluoroalkyl The objective of our study was to estimate the relationship concentrations and dental caries acid exposure and dental caries prevalence among between dental caries prevalence and exposure to four among US adolescents (NHANES adolescents, which, to the best of our knowledge, PFAA: perfluorooctanoic acid (PFOA), perfluorononanoic 1999–2012). BMJ Open has not been examined before. 2019;9:e024189. doi:10.1136/ acid (PFNA), perfluorohexane sulfonic acid (PFHxS) and ► The strengths of our study include the large sample perfluorooctane sulfonic acid (PFOS) in a nationally bmjopen-2018-024189 size (2869 participants) and the nationally repre- representative sample of US adolescents. Prepublication history and sentative nature of the National Health and Nutrition ► Setting/Design We analysed cross-sectional data from additional material for this Examination Survey (NHANES). the National Health and Nutrition Examination Survey from paper are available online. To ► Although we adjusted for potential confounders, 1999 to 2012 for 12–19-year-old US adolescents.
  • 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

    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.
  • PCSK9 Inhibitors – Clinical Applications

    PCSK9 Inhibitors – Clinical Applications

    VOLUME 39 : NUMBER 5 : OCTOBER 2016 EXPERIMENTAL AND CLINICAL PHARMACOLOGY PCSK9 inhibitors – clinical applications Robert Schmidli Consultant endocrinologist SUMMARY Department of Endocrinology The enzyme PCSK9 has an important role in regulating low-density lipoprotein (LDL) receptors Canberra Hospital and concentrations of LDL cholesterol. Inhibiting this enzyme could therefore reduce the incidence of ischaemic heart disease. Keywords The monoclonal antibodies alirocumab, evolocumab and bococizumab are directed against alirocumab, bococizumab, PCSK9 and inhibit its activity. Phase II trials have shown alirocumab and evolocumab to be evolocumab, ischaemic heart disease, LDL effective at lowering LDL cholesterol. cholesterol, proprotein Preliminary results of these phase II trials show potential benefits in ischaemic heart disease. convertase subtilisin/kexin type 9 Reports of adverse effects, including muscular symptoms and neurocognitive changes, were low. Large phase III cardiovascular outcome trials of these monoclonal antibodies will determine their Aust Prescr 2016;39:168–70 safety and efficacy. These drugs may have a role in the management of patients at very high risk http://dx.doi.org/10.18773/ of cardiovascular events such as those with familial hypercholesterolaemia. austprescr.2016.061 Introduction PCSK9 inhibitory antibodies The incidence of deaths from ischaemic heart disease Studies of uncommon mutations, such in Australia has reduced since the 1960s. While about as the LDL‑receptor mutations in familial half of this reduction is due to interventions such as hypercholesterolaemia, have led to important coronary revascularisation and secondary prevention, therapeutic advances in the study of lipids and the remainder is due to addressing risk factors such as cardiovascular disease. Proprotein convertase smoking, lipids and hypertension.
  • A61p1/16 (2006.01) A61p3/00 (2006.01) Km, Ml, Mr, Ne, Sn, Td, Tg)

    A61p1/16 (2006.01) A61p3/00 (2006.01) Km, Ml, Mr, Ne, Sn, Td, Tg)

    ( (51) International Patent Classification: TR), OAPI (BF, BJ, CF, CG, Cl, CM, GA, GN, GQ, GW, A61P1/16 (2006.01) A61P3/00 (2006.01) KM, ML, MR, NE, SN, TD, TG). A61K 31/192 (2006.01) C07C 321/28 (2006.01) Declarations under Rule 4.17: (21) International Application Number: — as to the applicant's entitlement to claim the priority of the PCT/IB2020/000808 earlier application (Rule 4.17(iii)) (22) International Filing Date: Published: 25 September 2020 (25.09.2020) — with international search report (Art. 21(3)) (25) Filing Language: English — before the expiration of the time limit for amending the claims and to be republished in the event of receipt of (26) Publication Language: English amendments (Rule 48.2(h)) (30) Priority Data: 62/906,288 26 September 2019 (26.09.2019) US (71) Applicant: ABIONYX PHARMA SA [FR/FR] ; 33-43 Av¬ enue Georges Pompidou, Batiment D, 31130 Bahna (FR). (72) Inventor: DASSEUX, Jean-Louis, Henri; 7 Allees Charles Malpel, Bat. B, 31300 Toulouse (FR). (74) Agent: HOFFMANN EITLE PATENT- UND RECHTSANWALTE PARTMBB, ASSOCIATION NO. 151; Arabellastrasse 30, 81925 Munich (DE). (81) Designated States (unless otherwise indicated, for every kind of national protection available) : AE, AG, AL, AM, AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IR, IS, IT, JO, JP, KE, KG, KH, KN, KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SA, SC, SD, SE, SG, SK, SL, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, WS, ZA, ZM, ZW.
  • 207/2015 3 Lääkeluettelon Aineet, Liite 1. Ämnena I Läkemedelsförteckningen, Bilaga 1

    207/2015 3 Lääkeluettelon Aineet, Liite 1. Ämnena I Läkemedelsförteckningen, Bilaga 1

    207/2015 3 LÄÄKELUETTELON AINEET, LIITE 1. ÄMNENA I LÄKEMEDELSFÖRTECKNINGEN, BILAGA 1. Latinankielinen nimi, Suomenkielinen nimi, Ruotsinkielinen nimi, Englanninkielinen nimi, Latinskt namn Finskt namn Svenskt namn Engelskt namn (N)-Hydroxy- (N)-Hydroksietyyli- (N)-Hydroxietyl- (N)-Hydroxyethyl- aethylprometazinum prometatsiini prometazin promethazine 2,4-Dichlorbenzyl- 2,4-Diklooribentsyyli- 2,4-Diklorbensylalkohol 2,4-Dichlorobenzyl alcoholum alkoholi alcohol 2-Isopropoxyphenyl-N- 2-Isopropoksifenyyli-N- 2-Isopropoxifenyl-N- 2-Isopropoxyphenyl-N- methylcarbamas metyylikarbamaatti metylkarbamat methylcarbamate 4-Dimethyl- ami- 4-Dimetyyliaminofenoli 4-Dimetylaminofenol 4-Dimethylaminophenol nophenolum Abacavirum Abakaviiri Abakavir Abacavir Abarelixum Abareliksi Abarelix Abarelix Abataceptum Abatasepti Abatacept Abatacept Abciximabum Absiksimabi Absiximab Abciximab Abirateronum Abirateroni Abirateron Abiraterone Acamprosatum Akamprosaatti Acamprosat Acamprosate Acarbosum Akarboosi Akarbos Acarbose Acebutololum Asebutololi Acebutolol Acebutolol Aceclofenacum Aseklofenaakki Aceklofenak Aceclofenac Acediasulfonum natricum Asediasulfoni natrium Acediasulfon natrium Acediasulfone sodium Acenocoumarolum Asenokumaroli Acenokumarol Acenocumarol Acepromazinum Asepromatsiini Acepromazin Acepromazine Acetarsolum Asetarsoli Acetarsol Acetarsol Acetazolamidum Asetatsoliamidi Acetazolamid Acetazolamide Acetohexamidum Asetoheksamidi Acetohexamid Acetohexamide Acetophenazinum Asetofenatsiini Acetofenazin Acetophenazine Acetphenolisatinum Asetofenoli-isatiini
  • The Opportunities and Challenges of Peroxisome Proliferator-Activated Receptors Ligands in Clinical Drug Discovery and Development

    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.
  • Integrative and Systemic Approaches for Evaluating Pparβ/Δ (PPARD)

    Integrative and Systemic Approaches for Evaluating Pparβ/Δ (PPARD)

    Integrative and systemic approaches for evaluating PPAR β/δ (PPARD) function Greta MP Giordano Attianese and Béatrice Desvergne Center for Integrative Genomics, University of Lausanne, Switzerland Footnotes: Corresponding author, BD: [email protected] Competing interests: The authors declare no competing financial interests Author contributions: Both authors have been involved in drafting the manuscript and revising it critically. Received December 5, 2014; Accepted March 9, 2015; Published April 27, 2015 Copyright © 2015 Giordano Attianese and Desvergne. This is an open-access article distributed under the terms of the Creative Commons Non-Commercial Attribution License, which permits unrestricted non-commercial use distribution and reproduction in any medium, provided the original work is properly cited. Abbreviations: αMyHC, α-Myosin Heavy Chain; BCL6, B-cell lymphoma 6 protein; BAT, Brown adipose tissue; ChIP, Chromatin Immunoprecipitation; CHD, Coronary heart disease; DBD, DNA-binding domain; FAO, Fatty Acid Oxidation; FA, Fatty Acid; GSIS, Glucose-stimulated insulin secretion; HSC, Hematopoietic Stem cells; H&E, Hematoxylin and Eosin; HDAC1, Histone deacetylase 1; LBD, Ligand binding domain; MCP1, Monocyte chemotactic protein 1; NFkB, Nuclear factor kappa-light-chain- enhancer of activated B cells; NR, Nuclear Receptor; NCoR1, Nuclear receptor co-repressor 1; PPARs, Peroxisome proliferator- activated receptors; PPRE, PPAR-responsive element; RER, Respiratory Exchange Ratio; RA, Retinoic Acid; RXR, Retinoid X receptor; SMRT, Silencing mediator of retinoic acid and thyroid hormone receptors; SNPs, Single Nucleotide Polymorphisms; SUMO, Small Ubiquitin-like Modifier; TZDs, Thiazolidinediones; TR, Thyroid hormone receptor; TG, Triglycerides; VLDL, Very large density lipoprotein; WOSCOPS, West of Scotland Coronary Prevention Study; WAT, White adipose tissue. Citation: Giordano Attianese G and Desvergne B (2015) Integrative and systemic approaches for evaluating PPAR β/δ (PPARD) function.
  • Research Article to Probe Full and Partial Activation

    Research Article to Probe Full and Partial Activation

    Hindawi PPAR Research Volume 2020, Article ID 5314187, 24 pages https://doi.org/10.1155/2020/5314187 Research Article To Probe Full and Partial Activation of Human Peroxisome Proliferator-Activated Receptors by Pan-Agonist Chiglitazar Using Molecular Dynamics Simulations Holli-Joi Sullivan,1 Xiaoyan Wang,2,3 Shaina Nogle,1 Siyan Liao,1,4 and Chun Wu 1 1College of Science and Mathematics, Rowan University, Glassboro, NJ 08028, USA 2School of Radiology, Taishan Medical University, Tai’an, Shandong 271016, China 3Medical School, Southeast University, Nanjing 210009, China 4Key Laboratory of Molecular Target & Clinical Pharmacology, School of Pharmaceutical Sciences, Guangzhou Medical University, Guangzhou 511436, China Correspondence should be addressed to Chun Wu; [email protected] Received 13 January 2020; Revised 25 February 2020; Accepted 3 March 2020; Published 1 April 2020 Academic Editor: Tom Hsun-Wei Huang Copyright © 2020 Holli-Joi Sullivan et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Chiglitazar is a promising new-generation insulin sensitizer with low reverse effects for the treatment of type II diabetes mellitus (T2DM) and has shown activity as a nonselective pan-agonist to the human peroxisome proliferator-activated receptors (PPARs) (i.e., full activation of PPARγ and a partial activation of PPARα and PPARβ/δ). Yet, it has no high-resolution complex structure with PPARs and its detailed interactions and activation mechanism remain unclear. In this study, we docked chiglitazar into three experimentally resolved crystal structures of hPPAR subtypes, PPARα, PPARβ/δ, and PPARγ, followed by 3 μs molecular dynamics simulations for each system.