DOCSLIB.ORG

FMO3 Inhibitors for Treating Pain

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text

Load more

(19) TZZ ___T (11) EP 2 674 161 A1 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 18.12.2013 Bulletin 2013/51 A61K 31/675 (2006.01) A61K 31/4164 (2006.01) A61P 29/00 (2006.01) (21) Application number: 13174939.2 (22) Date of filing: 11.11.2011 (84) Designated Contracting States: • Neely, Graham Gregory AL AT BE BG CH CY CZ DE DK EE ES FI FR GB Sydney, 2015 (AU) GR HR HU IE IS IT LI LT LU LV MC MK MT NL NO • McManus, Shane PL PT RO RS SE SI SK SM TR 1030 Vienna (AT) Designated Extension States: • Nilsson, Henrik BA ME 1030 Vienna (AT) (30) Priority: 11.11.2010 EP 10190922 (74) Representative: Sonn & Partner Patentanwälte Riemergasse 14 (62) Document number(s) of the earlier application(s) in 1010 Wien (AT) accordance with Art. 76 EPC: 11781808.8 / 2 637 649 Remarks: •This application was filed on 03-07-2013 as a (71) Applicant: Akron Molecules GmbH divisional application to the application mentioned 1030 Vienna (AT) under INID code 62. •Claims filed after the date of receipt of the divisional (72) Inventors: application (Rule 68(4) EPC). • Penninger, Josef 1130 Vienna (AT) (54) FMO3 inhibitors for treating pain (57) The present invention relates to new therapies to treat pain and related diseases, as well as pharmaceutical compounds for use in said therapies. EP 2 674 161 A1 Printed by Jouve, 75001 PARIS (FR) EP 2 674 161 A1 Description [0001] The present invention relates to the field of method of treatment of pain and the provision of pharmaceutical compounds suitable for such treatments. 5 [0002] Acute and chronic pain affects millions of people after injury or surgery and those suffering from diseases like arthritis, cancer, and diabetes. Nociception (the detection of noxious or damaging stimuli) serves a crucial biological purpose: it alerts living organisms to environmental dangers, inducing the sensation of pain, reflex withdrawal and complex behavioural and emotional responses, which protect the organism from further damage. Noxious stimuli are detected by specialized high threshold primary sensory neurons (nociceptors), which transfer signals to the spinal cord 10 and then transmit them to the brain for higher level processing that results in the conscious awareness of the sensation called pain. The functional importance of pain perception is exemplified by individuals with defects in nociception; patients with congenital insensitivity to pain do not survive past their twenties. [0003] Two basic types of pain can be distinguished - acute and chronic. Acute or nociceptive pain is generally self- limiting and serves a protective biological function by warning of ongoing tissue damage caused by noxious chemical, 15 thermal and mechanical stimuli. Examples of nociceptive pain include: postoperative pain, pain associated with trauma, and the pain associated with arthritis. Chronic pain, on the other hand, serves no protective biological function, and reflects either poor resolution of the painful stimuli, or is itself a disease process. Chronic pain is unrelenting and not self-limiting and can persist for years and even decades after the initial injury. Chronic pain is predominantly neuropathic in nature and may involve damage either to the peripheral or central nervous systems. 20 [0004] It is a goal of the present invention to provide methods of treating, ameliorating or suppressing pain, in particular by the use of novel compounds for this purpose. [0005] The present invention therefore provides the use of new classes of compounds for the treatment, prevention or reduction of pain. These compounds are given in the claims, and especially include Tenofovir (PMPA), dasatinib, AMG-706 ( motesanib ), BIRB 796 ( Doramapimod ), 569EKB- ( Pelitinib ), sorafenib , Vandetanib, 1033CI- 25 ( Canertinib ), NSC161613, N6-Benzyladenosine-5’-phosphate, p-Aminobenzoly PAB-J acid, NSC47091, cilomilast , Nicotinamide ( Nicotinamide ), IBMX, Roflumilast, Filaminast, Piclamilast, V11294, CC- 10004 ( Apremilast ), LAS31025 ( Arofylline ), CP80633 ( Atizoram ), Catramilast/Atopik ( Catramilast ), BRL-61063 ( Cimpyfylline ), Daxalipram/meso- pram ( Daxalipram ), Doxofylline, Drotaverine, Efloxate, Etamiphylline, Etazolate, Etofylline, Glaucine Hydrobromide ( Broncholytine ), GRC3886 ( oglemilast ), oxtriphyllin ( Choline theophyllinate ), Pumafentrine, Revamilast, Tofimilast, 30 Tolafentrine, Seoanin ( Trapidil ), GW 842470 (AWD 12-281), CDP-840, YM-976, CI-1018, D-4418, Lirimilast, SCH- 351591, RPL-554, IPL-455903 (HT-0712), GSK256066, Zardaverine, Vardenafil, OPC-6535 ( Tetomilast ), IC485, L- 826,141, ONO-6126, CI-1044, MK-0873, T-2585, R1533 (MEM-1414), Ronomilast ( ELB-353 ), UK-500,001, AN2728 , DE-103, Tofisopam, (R)-Tofisopam ( Dextofisopam ), (S)-Tofisopam ( Levotofisopam (USAN) ), EKB-568, SU-14813, LY-333531 ( Ruboxistaurin ), CGP- 52421, SKI-606 ( Bosutinib ), Roscovitine, Tenofovir (PMPA), Methimazole, Adefovir 35 dipivoxil (Bis-POM PMEA) ( Adefovir ), Acetazolamide, midostaurin ( PKC-412 ), tozasertib ( MK-0457, VX 680 ) or lestaurtinib ( CEP-701 ). A further compound is imatinib (STI-571), which is preferably used in the treatment on non- inflammatory pain, especially in the treatment of neuropathic pain. Alternative names or identification of the compounds are given in brackets. Chemical structures of some of these compounds are given as follows: 40 V11294 -[(3-cyclopentyloxy-4-methoxyphenyl) methyl]-N-ethyl-8-propan-2-ylpurin-6- amine: 45 50 55 2 EP 2 674 161 A1 (continued) GW 842470 (AWD 12-281) N-(3,5-dichloropyridin-4-yl)-2-[1-[(4- fluorophenyl)methyl]-5-hydroxyindol-3- 5 yl]-2-oxoacetamide 10 15 CDP-840 4- [(2R) -2- [3-(Cyclopentyloxy)-4- methoxyphenyl]-2-phenylethyl]-pyridine hydrochloride 20 25 YM-976 4-(3-Chlorophenyl)-1,7-diethylpyrido [2,3-d]pyrimidin-2(1H)-one 30 35 CI-1018 N-[9-Methyl-4-oxo-1-phenyl-3,4,6,7- tetrahydro-pyrrolo[3,2,1-jk][1,4] benzodiazepin-3(R)-yl]pyridine-4- carboxamide 40 D-4418 -(3,5-Dichloro-4-pyridinyl)-8- methoxyquinoline-5-carboxamid 45 50 55 3 EP 2 674 161 A1 (continued) SCH-351591 3,5-dichloro-4-(8-methoxy- 2-(trifluorome-thyl)quinolin-5-ylcarbox- 5 amido)pyridine-1-oxide 10 SCH 351591 RPL-554 N-{2-[(2E)-2-(mesitylimino)-9,10- 15 dimethoxy-4-oxo-6,7-dihydro-2H- pyrimido[6,1-a]-isoquinolin-3(4H)-yl] ethyl}urea 20 25 IPL-455903 (HT-0712) (3R,5R)-5-(3-(cyclopentyloxy)-4- methoxyphenyl)-3-(3-methylbenzyl) piperidin-2-one 30 35 GSK256066 6-[[3-[(Dimethyla-mino)carbonyl]phenyl] su lfonyl]-4-[(3-methoxyphenyl)amino]- 8-methyl-3-quinolinecarboxamide 40 OPC-6535 6-[2-(3,4-diethoxyphenyl)-1,3-thiazol-4- 45 yl]pyridine-2-carboxylic acid 50 55 4 EP 2 674 161 A1 (continued) L-826,141 4-[2-[3,4-Bis(difluoromethoxy)phe nyl]- 2-[4-[2,2,2-trifluoro-1-hydroxy- 5 1-(trifluorome-thyl)ethyl]phenyl]ethyl ]- 3-methylpyridine N-oxide 10 L-826,141 (Enantiomer 1) CI-1044 N-(9-amino-4-oxo-1-phenyl-3,4,6,7- tetrahydro(1,4)diazepin o(6,7,1-hi)indol- 15 3-yl)nicotinamide 20 MK-0873 (-)-trans-2-(3’-(3-(N-Cycloprpropylcarbamoyl)-4-oxo-1,4-dihydro-1,8-naphthyridin-1- yl)-3-fluorobiphenyl-4-yl) cycloprpanecarboxylic acid T-2585 25 30 AN2728 5-(4-cyanophenoxy)-2,3-dihydro-1- hydroxy-2,1-benzoxaborole 35 40 SU-14813 (S,Z)-5-((5-fluoro-2-oxoindolin-3- ylidene)methyl)-N-(2-hydroxy-3- morpholinopropyl)-2,4-dimethyl-1H- pyrrole-3-carboxamide 45 50 55 5 EP 2 674 161 A1 (continued) CGP-52421 5 10 15 NSC161613 2-[[2-[(2-aminoacetyl)amino]-3-(2,4- dinitrophenyl)sulfanylp ropanoyl]amino] 20 pentaned ioic acid 25 30 NSC47091 2-(3-carboxyprop-2-enoylamino)- 6-[[(2)-3-carboxyprop-2-enoyl]amino] benzoic acid 35 40 [0006] In preferred embodiments the inventive compound is an inhibitor (i.e. an antagonist) or modulator of any one of FRK, PDE4D, LPAR3, CAMK1D, CSNK1G3 or FMO3. Inhibitors or ligands (i.e. binders) or modulators of FRK, PDE4D, LPAR3, CAMK1D, CSNK1G3 or FMO3 can be used in the treatment of pain in a subject. In preferred embodiments the FRK, PDE4D, LPAR3, CAMK1D, CSNK1G3 or FMO3 modulator is a selective FRK, PDE4D, LPAR3, CAMK1D, 45 CSNK1G3 or FMO3 modulator. By "selective" it is meant that the affinity for one of FRK, PDE4D, LPAR3, CAMK1D or FMO3 is at least 10-fold, preferably 25-fold, more preferred 100-fold, still preferred 150-fold higher than the affinity of the other targets selected from FRK, PDE4D, LPAR3, CAMK1D or FMO3. [0007] Surprisingly it has been shown that some of these targets, such as FRK, FMO3, LPAR3 can be both activated, e.g. by an agonist, or inhibited (e.g. by an inhibitor or antagonist) for an anti-pain effect in a patient. The group of agonists 50 and antagonists is refered to herein as "modulators". Although in most cases an inhibitor is preferred for greater effect, it seems that modulation of activity of these targets in any direction reduces the pain or sensation of pain. Preferably the modulator is a strong binder to these targets, especially with a Kd of 1000nM or less or an IC50 of 1000 nM or less. Preferred lower values for Kd and IC50 are 800 nM or less, 600 nM or less, 500 nM or less, 400 nM or less, 300 nM or less, 200 nM or less, 100 nM or less, 50 nM or less or even 30 nM or less. 55 [0008] In particular preferred are FMO3 modulators or inhibitors for use in the treatment of pain. Such compounds are e.g. Tenofovir and Methimazole. [0009] In particular preferred are FRK modulators or inhibitors for use in the treatment of pain. Such compounds are 6 EP 2 674 161 A1 e.g. dasatinib, motesanib, Doramapimod, Pelitinib, sorafenib, Vandetanib and Canertinib. [0010] Preferably the inhibitor is selected from compounds with a Kd of lower than 3000 nM, preferably lower than 2000 nM, especially preferred lower than 1000 nM.
Recommended publications
  • Investigation of Key Genes and Pathways in Inhibition of Oxycodone on Vincristine-Induced Microglia Activation by Using Bioinformatics Analysis

    Investigation of Key Genes and Pathways in Inhibition of Oxycodone on Vincristine-Induced Microglia Activation by Using Bioinformatics Analysis

    Hindawi Disease Markers Volume 2019, Article ID 3521746, 10 pages https://doi.org/10.1155/2019/3521746 Research Article Investigation of Key Genes and Pathways in Inhibition of Oxycodone on Vincristine-Induced Microglia Activation by Using Bioinformatics Analysis Wei Liu,1 Jishi Ye,2 and Hong Yan 1 1Department of Anesthesiology, the Central Hospital of Wuhan, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430014, China 2Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, 430060 Hubei, China Correspondence should be addressed to Hong Yan; [email protected] Received 2 November 2018; Accepted 31 December 2018; Published 10 February 2019 Academic Editor: Hubertus Himmerich Copyright © 2019 Wei Liu 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. Introduction. The neurobiological mechanisms underlying the chemotherapy-induced neuropathic pain are only partially understood. Among them, microglia activation was identified as the key component of neuropathic pain. The aim of this study was to identify differentially expressed genes (DEGs) and pathways associated with vincristine-induced neuropathic pain by using bioinformatics analysis and observe the effects of oxycodone on these DEG expressions in a vincristine-induced microglia activation model. Methods. Based on microarray profile GSE53897, we identified DEGs between vincristine-induced neuropathic pain rats and the control group. Using the ToppGene database, the prioritization DEGs were screened and performed by gene ontology (GO) and signaling pathway enrichment. A protein-protein interaction (PPI) network was used to explore the relationship among DEGs.
  • Effects of Febuxostat on Autistic Behaviors and Computational Investigations of Diffusion and Pharmacokinetics

    Effects of Febuxostat on Autistic Behaviors and Computational Investigations of Diffusion and Pharmacokinetics

    Effects of Febuxostat on Autistic Behaviors and Computational Investigations of Diffusion and Pharmacokinetics Jamelle M. Simmons Dissertation submitted to the Faculty of the Virginia Polytechnic Institute and State University in partial fulfillment of the requirements for the degree of Doctor of Philosophy in Biomedical Engineering Yong W. Lee, Chair Luke E. Achenie Hampton C. Gabler Alexei Morozov Aaron S. Goldstein John H. Rossmeisl November 27, 2018 Blacksburg, Virginia Keywords: Autism Spectrum Disorder, Xanthine Oxidase, Reactive Oxygen Species, Pharmacokinetics, Animal Behavior Copyright 2019, Jamelle M. Simmons Effects of Febuxostat on Autistic Behaviors and Computational Investigations of Diffusion and Pharmacokinetics Jamelle M. Simmons (ABSTRACT) Autism spectrum disorder (ASD) is a lifelong disability that has seen a rise in prevalence from 1 in 150 children to 1 in 59 between 2000 and 2014. Patients show behavioral ab- normalities in the areas of social interaction, communication, and restrictive and repetitive behaviors. As of now, the exact cause of ASD is unknown and literature points to multiple causes. The work contained within this dissertation explored the reduction of oxidative stress in brain tissue induced by xanthine oxidase (XO). Febuxostat is a new FDA approved XO- inhibitor that has been shown to be more selective and potent than allopurinol in patients with gout.The first study developed a computational model to calculate an effective diffu- sion constant (Deff ) of lipophilic compounds, such as febuxostat, that can cross endothelial cells of the blood-brain barrier (BBB) by the transcellular pathway. In the second study, male juvenile autistic (BTBR) mice were treated with febuxostat for seven days followed by behavioral testing and quantification of oxidative stress in brain tissue compared to controls.
  • Activity of Selected Group of Monoterpenes in Alzheimer's

    Activity of Selected Group of Monoterpenes in Alzheimer's

    International Journal of Molecular Sciences Review Activity of Selected Group of Monoterpenes in Alzheimer’s Disease Symptoms in Experimental Model Studies—A Non-Systematic Review Karolina Wojtunik-Kulesza 1,*, Monika Rudkowska 2, Kamila Kasprzak-Drozd 1,* , Anna Oniszczuk 1 and Kinga Borowicz-Reutt 2 1 Department of Inorganic Chemistry, Medical University of Lublin, Chod´zki4a, 20-093 Lublin, Poland; [email protected] 2 Independent Experimental Neuropathophysiology Unit, Medical University of Lublin, Jaczewskiego 8b, 20-090 Lublin, Poland; [email protected] (M.R.); [email protected] (K.B.-R.) * Correspondence: [email protected] (K.W.-K.); [email protected] (K.K.-D.) Abstract: Alzheimer’s disease (AD) is the leading cause of dementia and cognitive function im- pairment. The multi-faced character of AD requires new drug solutions based on substances that incorporate a wide range of activities. Antioxidants, AChE/BChE inhibitors, BACE1, or anti-amyloid platelet aggregation substances are most desirable because they improve cognition with minimal side effects. Plant secondary metabolites, used in traditional medicine and pharmacy, are promising. Among these are the monoterpenes—low-molecular compounds with anti-inflammatory, antioxidant, Citation: Wojtunik-Kulesza, K.; enzyme inhibitory, analgesic, sedative, as well as other biological properties. The presented review Rudkowska, M.; Kasprzak-Drozd, K.; focuses on the pathophysiology of AD and a selected group of anti-neurodegenerative monoterpenes Oniszczuk, A.; Borowicz-Reutt, K. and monoterpenoids for which possible mechanisms of action have been explained. The main body Activity of Selected Group of of the article focuses on monoterpenes that have shown improved memory and learning, anxiolytic Monoterpenes in Alzheimer’s and sleep-regulating effects as determined by in vitro and in silico tests—followed by validation in Disease Symptoms in Experimental in vivo models.
  • Potential Metabolic Effect of Sucralose Following an Oral Glucose Load in Subjects with Obesity and Normal-Weight Subjects

    Potential Metabolic Effect of Sucralose Following an Oral Glucose Load in Subjects with Obesity and Normal-Weight Subjects

    POTENTIAL METABOLIC EFFECT OF SUCRALOSE FOLLOWING AN ORAL GLUCOSE LOAD IN SUBJECTS WITH OBESITY AND NORMAL-WEIGHT SUBJECTS BY ALEXANDER DANIEL NICHOL THESIS Submitted in partial fulfillment of the requirements for the degree of Master of Science in Food Science and Human Nutrition with a concentration in Human Nutrition in the Graduate College of the University of Illinois at Urbana-Champaign, 2018 Urbana, Illinois Master’s Committee: Assistant Professor M. Yanina Pepino de Gruev, Chair Assistant Professor Megan J. Dailey Professor Emeritus John W. Erdman ABSTRACT Objective: Whether sucralose, the most commonly used non-nutritive sweetener (NNS), affects glucose metabolism in people is unclear. It has been reported that, when consumed acutely before an oral glucose tolerance test (OGTT), sucralose enhances insulinemic responses and decreases insulin sensitivity in subjects with obesity who are not regular consumers of NNS. However, studies in normal-weight adults, none of which control for use of NNS, found sucralose does not affect insulin responses to the ingestion of glucose or other carbohydrates. The objectives of the current study are to determine if those effects of sucralose can be replicated in subjects with obesity, are generalizable to normal-weight subjects when controlling for history of NNS use, and are caused merely by the sweet taste of sucralose (i.e., sham-feeding). In addition, with the aim of identifying potential mechanisms by which sucralose may decrease postprandial insulin sensitivity, we here investigated whole-body glucose kinetics by using a dual-tracer approach. Finally, we tested the hypothesis that, due to the compromised intestinal permeability associated with obesity, sucralose consumption is associated with higher plasma sucralose concentrations in people with obesity.
  • ULORIC Safely and Effectively

    ULORIC Safely and Effectively

    HIGHLIGHTS OF PRESCRIBING INFORMATION -------------------------WARNINGS AND PRECAUTIONS-------------------­ These highlights do not include all the information needed to use ULORIC safely and effectively. See full prescribing • Cardiovascular Death: In a CV outcomes study, there was a higher information for ULORIC. rate of CV death in patients treated with ULORIC compared to allopurinol; in the same study ULORIC was non-inferior to ULORIC (febuxostat) tablets, for oral use allopurinol for the primary endpoint of major adverse Initial U.S. Approval: 2009 cardiovascular events (MACE). Consider the risks and benefits of WARNING: CARDIOVASCULAR DEATH ULORIC when deciding to prescribe or continue patients on See full prescribing information for complete boxed warning. ULORIC. (1, 5.1) • Gout patients with established cardiovascular (CV) disease • Gout Flares: An increase in gout flares is frequently observed treated with ULORIC had a higher rate of CV death compared to during initiation of anti-hyperuricemic agents, including ULORIC. If those treated with allopurinol in a CV outcomes study. (5.1) a gout flare occurs during treatment, ULORIC need not be discontinued. Prophylactic therapy (i.e., non-steroidal anti- • Consider the risks and benefits of ULORIC when deciding to inflammatory drug [NSAID] or colchicine upon initiation of prescribe or continue patients on ULORIC. ULORIC should only treatment) may be beneficial for up to six months. (2.4, 5.2) be used in patients who have an inadequate response to a maximally titrated dose of allopurinol, who are intolerant to • Hepatic Effects: Postmarketing reports of hepatic failure, allopurinol, or for whom treatment with allopurinol is not sometimes fatal. Causality cannot be excluded.
  • Supplementary Information

    Supplementary Information

    Supplementary Information Network-based Drug Repurposing for Novel Coronavirus 2019-nCoV Yadi Zhou1,#, Yuan Hou1,#, Jiayu Shen1, Yin Huang1, William Martin1, Feixiong Cheng1-3,* 1Genomic Medicine Institute, Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA 2Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine, Case Western Reserve University, Cleveland, OH 44195, USA 3Case Comprehensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA #Equal contribution *Correspondence to: Feixiong Cheng, PhD Lerner Research Institute Cleveland Clinic Tel: +1-216-444-7654; Fax: +1-216-636-0009 Email: [email protected] Supplementary Table S1. Genome information of 15 coronaviruses used for phylogenetic analyses. Supplementary Table S2. Protein sequence identities across 5 protein regions in 15 coronaviruses. Supplementary Table S3. HCoV-associated host proteins with references. Supplementary Table S4. Repurposable drugs predicted by network-based approaches. Supplementary Table S5. Network proximity results for 2,938 drugs against pan-human coronavirus (CoV) and individual CoVs. Supplementary Table S6. Network-predicted drug combinations for all the drug pairs from the top 16 high-confidence repurposable drugs. 1 Supplementary Table S1. Genome information of 15 coronaviruses used for phylogenetic analyses. GenBank ID Coronavirus Identity % Host Location discovered MN908947 2019-nCoV[Wuhan-Hu-1] 100 Human China MN938384 2019-nCoV[HKU-SZ-002a] 99.99 Human China MN975262
  • List of Union Reference Dates A

    List of Union Reference Dates A

    Active substance name (INN) EU DLP BfArM / BAH DLP yearly PSUR 6-month-PSUR yearly PSUR bis DLP (List of Union PSUR Submission Reference Dates and Frequency (List of Union Frequency of Reference Dates and submission of Periodic Frequency of submission of Safety Update Reports, Periodic Safety Update 30 Nov. 2012) Reports, 30 Nov.
  • Sweetness Perception Is Not Involved in the Regulation of Blood Glucose After Oral Application of Sucrose and Glucose Solutions in Healthy Male Subjects

    Sweetness Perception Is Not Involved in the Regulation of Blood Glucose After Oral Application of Sucrose and Glucose Solutions in Healthy Male Subjects

    RESEARCH ARTICLE www.mnf-journal.com Sweetness Perception is not Involved in the Regulation of Blood Glucose after Oral Application of Sucrose and Glucose Solutions in Healthy Male Subjects Verena Grüneis, Kerstin Schweiger, Claudia Galassi, Corinna M. Karl, Julia Treml, Jakob P. Ley, Jürgen König, Gerhard E. Krammer, Veronika Somoza, and Barbara Lieder* 1. Introduction Scope: This study investigates the effect of the sweetness of a sucrose versus an isocaloric glucose solution in dietary concentrations on blood glucose Sweet taste is innately highly preferred regulation by adjusting the sweetness level using the sweet taste inhibitor by humans, but the global excessive con- sumption of sweet tasting carbohydrates lactisole. largely contributes to the overall energy Methods and Results: A total of 27 healthy males participated in this intake,[1] leading to an increased risk randomized, crossover study with four treatments: 10% glucose, 10% for obesity and comorbidities like type sucrose, 10% sucrose + 60 ppm lactisole, and 10% glucose + 60 ppm 2 diabetes.[2] One of the main sources lactisole. Plasma glucose, insulin, glucagon-like peptide 1, and glucagon for dietary sugars are sugar-sweetened beverages like fruit drinks, lemonades, levels are measured at baseline and 15, 30, 60, 90, and 120 min after beverage and ice tea.[3] Beside the caloric load, the consumption. Test subjects rated the sucrose solution to be sweeter than the consumption of such sugar-sweetened isocaloric glucose solution, whereas no difference in sweetness is reported beverages is associated with the expo- after addition of lactisole to the sucrose solution. Administration of the less sure to a high level of sweetness.
  • )&F1y3x PHARMACEUTICAL APPENDIX to THE

    )&F1y3x PHARMACEUTICAL APPENDIX to THE

    )&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 ACTODIGIN 36983-69-4 ABANOQUIL 90402-40-7 ADAFENOXATE 82168-26-1 ABCIXIMAB 143653-53-6 ADAMEXINE 54785-02-3 ABECARNIL 111841-85-1 ADAPALENE 106685-40-9 ABITESARTAN 137882-98-5 ADAPROLOL 101479-70-3 ABLUKAST 96566-25-5 ADATANSERIN 127266-56-2 ABUNIDAZOLE 91017-58-2 ADEFOVIR 106941-25-7 ACADESINE 2627-69-2 ADELMIDROL 1675-66-7 ACAMPROSATE 77337-76-9 ADEMETIONINE 17176-17-9 ACAPRAZINE 55485-20-6 ADENOSINE PHOSPHATE 61-19-8 ACARBOSE 56180-94-0 ADIBENDAN 100510-33-6 ACEBROCHOL 514-50-1 ADICILLIN 525-94-0 ACEBURIC ACID 26976-72-7 ADIMOLOL 78459-19-5 ACEBUTOLOL 37517-30-9 ADINAZOLAM 37115-32-5 ACECAINIDE 32795-44-1 ADIPHENINE 64-95-9 ACECARBROMAL 77-66-7 ADIPIODONE 606-17-7 ACECLIDINE 827-61-2 ADITEREN 56066-19-4 ACECLOFENAC 89796-99-6 ADITOPRIM 56066-63-8 ACEDAPSONE 77-46-3 ADOSOPINE 88124-26-9 ACEDIASULFONE SODIUM 127-60-6 ADOZELESIN 110314-48-2 ACEDOBEN 556-08-1 ADRAFINIL 63547-13-7 ACEFLURANOL 80595-73-9 ADRENALONE
  • 4 Supplementary File

    4 Supplementary File

    Supplemental Material for High-throughput screening discovers anti-fibrotic properties of Haloperidol by hindering myofibroblast activation Michael Rehman1, Simone Vodret1, Luca Braga2, Corrado Guarnaccia3, Fulvio Celsi4, Giulia Rossetti5, Valentina Martinelli2, Tiziana Battini1, Carlin Long2, Kristina Vukusic1, Tea Kocijan1, Chiara Collesi2,6, Nadja Ring1, Natasa Skoko3, Mauro Giacca2,6, Giannino Del Sal7,8, Marco Confalonieri6, Marcello Raspa9, Alessandro Marcello10, Michael P. Myers11, Sergio Crovella3, Paolo Carloni5, Serena Zacchigna1,6 1Cardiovascular Biology, 2Molecular Medicine, 3Biotechnology Development, 10Molecular Virology, and 11Protein Networks Laboratories, International Centre for Genetic Engineering and Biotechnology (ICGEB), Padriciano, 34149, Trieste, Italy 4Institute for Maternal and Child Health, IRCCS "Burlo Garofolo", Trieste, Italy 5Computational Biomedicine Section, Institute of Advanced Simulation IAS-5 and Institute of Neuroscience and Medicine INM-9, Forschungszentrum Jülich GmbH, 52425, Jülich, Germany 6Department of Medical, Surgical and Health Sciences, University of Trieste, 34149 Trieste, Italy 7National Laboratory CIB, Area Science Park Padriciano, Trieste, 34149, Italy 8Department of Life Sciences, University of Trieste, Trieste, 34127, Italy 9Consiglio Nazionale delle Ricerche (IBCN), CNR-Campus International Development (EMMA- INFRAFRONTIER-IMPC), Rome, Italy This PDF file includes: Supplementary Methods Supplementary References Supplementary Figures with legends 1 – 18 Supplementary Tables with legends 1 – 5 Supplementary Movie legends 1, 2 Supplementary Methods Cell culture Primary murine fibroblasts were isolated from skin, lung, kidney and hearts of adult CD1, C57BL/6 or aSMA-RFP/COLL-EGFP mice (1) by mechanical and enzymatic tissue digestion. Briefly, tissue was chopped in small chunks that were digested using a mixture of enzymes (Miltenyi Biotec, 130- 098-305) for 1 hour at 37°C with mechanical dissociation followed by filtration through a 70 µm cell strainer and centrifugation.
  • Phosphodiesterase (PDE)

    Phosphodiesterase (PDE)

    Phosphodiesterase (PDE) Phosphodiesterase (PDE) is any enzyme that breaks a phosphodiester bond. Usually, people speaking of phosphodiesterase are referring to cyclic nucleotide phosphodiesterases, which have great clinical significance and are described below. However, there are many other families of phosphodiesterases, including phospholipases C and D, autotaxin, sphingomyelin phosphodiesterase, DNases, RNases, and restriction endonucleases, as well as numerous less-well-characterized small-molecule phosphodiesterases. The cyclic nucleotide phosphodiesterases comprise a group of enzymes that degrade the phosphodiester bond in the second messenger molecules cAMP and cGMP. They regulate the localization, duration, and amplitude of cyclic nucleotide signaling within subcellular domains. PDEs are therefore important regulators ofsignal transduction mediated by these second messenger molecules. www.MedChemExpress.com 1 Phosphodiesterase (PDE) Inhibitors, Activators & Modulators (+)-Medioresinol Di-O-β-D-glucopyranoside (R)-(-)-Rolipram Cat. No.: HY-N8209 ((R)-Rolipram; (-)-Rolipram) Cat. No.: HY-16900A (+)-Medioresinol Di-O-β-D-glucopyranoside is a (R)-(-)-Rolipram is the R-enantiomer of Rolipram. lignan glucoside with strong inhibitory activity Rolipram is a selective inhibitor of of 3', 5'-cyclic monophosphate (cyclic AMP) phosphodiesterases PDE4 with IC50 of 3 nM, 130 nM phosphodiesterase. and 240 nM for PDE4A, PDE4B, and PDE4D, respectively. Purity: >98% Purity: 99.91% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 1 mg, 5 mg Size: 10 mM × 1 mL, 10 mg, 50 mg (R)-DNMDP (S)-(+)-Rolipram Cat. No.: HY-122751 ((+)-Rolipram; (S)-Rolipram) Cat. No.: HY-B0392 (R)-DNMDP is a potent and selective cancer cell (S)-(+)-Rolipram ((+)-Rolipram) is a cyclic cytotoxic agent. (R)-DNMDP, the R-form of DNMDP, AMP(cAMP)-specific phosphodiesterase (PDE) binds PDE3A directly.
  • Lung Inflammation and Atopy Muscarinic Receptor Expression

    Lung Inflammation and Atopy Muscarinic Receptor Expression

    The Journal of Immunology Maternal Exposure to Secondhand Cigarette Smoke Primes the Lung for Induction of Phosphodiesterase-4D5 Isozyme and Exacerbated Th2 Responses: Rolipram Attenuates the Airway Hyperreactivity and Muscarinic Receptor Expression but Not Lung Inflammation and Atopy1 Shashi P. Singh,* Neerad C. Mishra,* Jules Rir-sima-ah,* Mathew Campen,* Viswanath Kurup,† Seddigheh Razani-Boroujerdi,* and Mohan L. Sopori2* Airway hyperreactivity (AHR), lung inflammation, and atopy are clinical signs of allergic asthma. Gestational exposure to ciga- rette smoke (CS) markedly increases the risk for childhood allergic asthma. Muscarinic receptors regulate airway smooth muscle tone, and asthmatics exhibit increased AHR to muscarinic agonists. We have previously reported that in a murine model of bronchopulmonary aspergillosis, maternal exposure to mainstream CS increases AHR after acute intratracheal administration of Aspergillus fumigatus extract. However, the mechanism by which gestational CS induces allergic asthma is unclear. We now show for the first time that, compared with controls, mice exposed prenatally to secondhand CS exhibit increased lung inflammation (predominant infiltration by eosinophils and polymorphs), atopy, and airway resistance, and produce proinflammatory cytokines (IL-4, IL-5, IL-6, and IL-13, but not IL-2 or IFN-␥). These changes, which occur only after an allergen (A. fumigatus extract) treatment, are correlated with marked up-regulated lung expression of M1, M2, and M3 muscarinic receptors and phosphodi- esterase (PDE)4D5 isozyme. Interestingly, the PDE4-selective inhibitor rolipram attenuates the increase in AHR, muscarinic receptors, and PDE4D5, but fails to down-regulate lung inflammation, Th2 cytokines, or serum IgE levels. Thus, the fetus is extraordinarily sensitive to CS, inducing allergic asthma after postnatal exposure to allergens.