Thiazolidinediones

Total Page:16

File Type:pdf, Size:1020Kb

Thiazolidinediones Combining molecular modelling with experiments: Sulfonylureas and glinides as new PPARγ agonists Marco Scarsi Biozentrum - Swiss Institute of Bioinformatics Drug discovery and development 12-15 years of work 5-6 years 5-6 years 1-2 years Registration Preclinical Candidate Clinical tests Drug and research drugs marketing Pre-clinical drug research: Real and virtual Optimization Target Molecular DB Candidate toxicology identification screening drugs metabolism Optimization Target Molecular DB Candidate toxicology identification screening drugs Optimizationmetabolism Target Molecular DB Candidate toxicology identification screening drugs 1-2 years 1 year 3-4metabolism years Virtual screening ? DB Does the molecule bind to the protein? Virtual screening • Principles of molecular mechanics: – Atoms as basic units – Chemical bonds cannot be broken: They can be stretched, bent, torqued. – Good to simulate non-covalent binding AutoDock • The potential generated by the protein is calculated on a grid • Each ligand is flexibly sampled on the grid (conformational search) AutoDock: algorithm • Lamarckian Genetic Algorithm • The searcher modifies the phenotype, which is allowed to update the genotype • Lamarck: “an adaptation of an individual to its environment can be inherited by its offsprings” Our work… Virtual Target screening of Experimental Drug selection: known drugs validation redirection PPARγ • Identify new PPARγ ligands among known drugs • TheraSTrat was interested in side-effects of known drugs Nuclear receptors Ligands: Nuclear receptor Response Element PPARγ • Pharmacological target for type-II diabetes (several drugs on the market) • It controls lipid metabolism and glucose homeostasis • Lots of experimental data available PPARγ agonists Fatty acid (endogenous) Thiazolidinedione Tyrosine-based (drug) agonist (candidate drug) X-ray: PPARγ bound to farglitazar HIS 323 TYR 473 SER 289 HIS 449 Farglitazar: potent synthetic agonist (nM) Mutations is SER289, HIS323, TYR473, HIS449 strongly reduce activity Agonists aligned (X-ray) • Is there anything else binding to PPARγ ? • Virtual screening Compound libraries • TheraSTrat AG database: ~8000 compounds – most marketed drugs – proprietary • Chembank database: ~6000 compounds – bioactive compounds – freely available Virtual screening on a grid Docking a ligand to the receptor CSCS [BC]2 PC Desktop Grid (PBS) (UD MP, Win32) Grid Manager Ticino Basel [BC]2 HPC cluster Vital-IT HPC cluster (SGE, x86-32) (LSF, Itanium 64) Basel Lausanne Docking results • Sulfonylureas and glinides bind to PPARγ Gliquidone Repaglinide Farglitazar (x-ray) Glipizide Nateglinide Glimepiride Mitiglinide • Why are sulfonylureas and glinides so interesting as putative PPARγ agonists? Type II Diabetes: drug therapies PPARγ Sulfonylureas, agonists Glinides ? Bind to sulfonylurea Bind to PPARγ receptor Reduce insulin Improve insulin resistance secretion Type II diabetes treatment Experimental validation 3 experiments: biochemistry • Binding to receptor – displacement of labeled ligand • Activation of receptor – transactivation assays • Activation of metabolic cell biology pathways – expression of PPARγ-regulated genes PPARγ Binding Assays • PPARγ + fluorescent labeled high-affinity ligand • Competitor assay Results of Binding Assays Sulfonylureas Glinides Gliquidone IC50 = 8μM Nateglinide IC50 = 316μM 120 120 100 100 80 80 60 60 40 40 Ar(%) 20 Ar(%) 20 0 0 -20 -20 0.001 0.1 10 1000 0.001 0.1 10 1000 Compound (µM) Compound (µM) ...and ...and Glimepiride IC50 = 125μM Repaglinide IC50 > 1.5mM IC50 ? Glipizide IC50 ? Mitiglinide Activation of receptor • Transactivation Ligand assay Expression PPAR Vector • Measure ligand effect on synthetic PPAR RXR PPARE target gene light emitted by luciferin/luciferase LUC reaction measured by photometer Reporter vector Results of transactivation assays Sulfonylureas Glinides 16 14 4 12 3 10 8 2 6 Fold activation Fold activation 4 Gliquidone 1 Repaglinide 2 Glipizide Nateglinide Mitiglinide 0 Glimepiride 0 0.001 0.01 0.1 1 10 100 1000 0.001 0.01 0.1 1 10 100 1000 Concentration (µM)m Concentration (µM) ÎSulfonylureas and glinides activate PPARγ in the 10-100 mM range PPARγ-dependent gene activation • Mouse pre-adipocyte cells • Measure expression of selected genes induced by PPARγ signaling: – Adiponectin –aP2 –GLUT4 PPARγ-dependent gene activation 100 90 80 70 adiponectin 60 50 aP2 40 GLUT4 30 20 10 0 % of induction rosiglitazone induction % of glipizide 100 nateglinide 50 gliquidone 10 pioglitazone 10 microM microM microM microM Sulfonylureas and Glinides Known PPARγ activator Experiments: Summary biochemistry • Sulfonylureas and glinides: – bind to PPARγ – activate PPARγ and cell biology enhance transcription Clinically relevant? •PPARγ activation observed at concentrations of 10-100 μM • Do these drugs ever reach these plasma concentrations? • Yes (gliquidone, glipizide, nateglinide) Type II Diabetes: drug therapies Glitazones, Sulfonylureas, TZDs Glinides Bind to sulfonylurea Activate PPARγ receptor Reduce insulin Improve insulin resistance secretion type II diabetes treatment Conclusion: Chemical – carboxylic acids known PPARγ agonists – thiazolidinediones – sulfonylureas new • Same acidity: – carboxylic acids pKa ~4.8 – thiazolidinediones pKa ~6.5 – sulfonylureas pKa ~5.3 • Same network of H-bonds Conclusions: Pharmacological • Sulfonylurea and glinide drugs can: – Enhance insulin secretion (SU receptor) – Reduce insulin resistance (PPARγ) • Possible to design new drugs targeting PPARγ and the SU receptor • A "favorable side effect"? A broad sinergy Michael Podvinec Adrian Roth Renate Looser Urs A. Meyer Torsten Schwede Christoph Ruecker TheraSTrat Hubert Hug Hugo Albrecht Sander Kersten Patent? Hard to patent: Patentable: Disease 1 Disease 1 Disease 2 Pre-clinical research: real and virtual High- Target Lead Candidate throughput Leads Toxicology, identification optimization drugs screening metabolism High- Target Lead Candidate throughput Leads Toxicology, identification optimization drugs screening metabolism High- Target Lead Candidate throughput Leads Toxicology, 1-2identification years 1 year 2-3optimization years 1-2 years drugs screening metabolism.
Recommended publications
  • Download Product Catalog
    Total Quality Medications Product Portfolio Rx Product name Dosage form Generic name Pack size Indications A- Alimentary tract and metabolism A02B – Proton pump inhibitor Omecarbex 20 mg H.G Cap Omeprazole +Na 20 Caps Acid reflux and Ulcers Omecarbex 40 mg H.G Cap Carbonate 20 Caps Acid reflux and Ulcers A06A - Laxatives Amiprostone 8 mcg S.G Cap Lubiprostone 20 Capsules Laxative Amiprostone 24 mcg S.G Cap Lubiprostone 10 Capsules Laxative A07A- Intestinal Anti-infective Anti-diarrheal Gastrobiotic 200 mg Tablets Rifiximin 20 Tablets Antidiarrheal Gastrobiotic 550 mg Tablets Rifiximin 30 Tablets Antidiarrheal Nitazode 100 mg/5 ml Suspension Nitazoxanide Bottle 60 ml Antiprotozoal A10B- Oral Anti -diabetics A10-BD - Oral hypoglycemic associations Glimepiride+ Improve glycemic control for type 2 Glimepiride plus 4/30 Tablets 30 Tablets Pioglitazone Hcl diabetes Glimepiride+ Improve glycemic control for type 2 Glimepiride plus 2/30 Tablets 30 Tablets Pioglitazone Hcl diabetes Metformin Hcl + Improve glycemic control for type 2 Bioglitaplus 15/500 Tablets 20 Tablets Pioglitazone Hcl diabetes Metformin Hcl + Improve glycemic control for type 2 Bioglitaplus 15/850 Tablets 20 Tablets Pioglitazone Hcl diabetes A10BX - Other anti diabetics Control the elevation of blood sugar Megy One 10 mg Tablets Mitiglinide 20 Tablets after eating B- Blood and blood forming organs B01A - Anti-thrombotic agents Andorivaban 10 mg F.C Tablets Rivaroxaban 20 Tablets Anticoagulants Andorivaban 15 mg F.C Tablets Rivaroxaban 20 Tablets Anticoagulants Andorivaban 20
    [Show full text]
  • Specifications of Approved Drug Compound Library
    Annexure-I : Specifications of Approved drug compound library The compounds should be structurally diverse, medicinally active, and cell permeable Compounds should have rich documentation with structure, Target, Activity and IC50 should be known Compounds which are supplied should have been validated by NMR and HPLC to ensure high purity Each compound should be supplied as 10mM solution in DMSO and at least 100µl of each compound should be supplied. Compounds should be supplied in screw capped vial arranged as 96 well plate format.
    [Show full text]
  • Enhancement of Dissolution and Oral Bioavailability of Gliquidone with Hydroxy Propyl-Β-Cyclodextrin
    ORIGINAL ARTICLES Pharmacology Division, Indian Institute of Chemical Technology, Hyderabad, India Enhancement of dissolution and oral bioavailability of gliquidone with hydroxy propyl-b-cyclodextrin S. Sridevi, A. S. Chauhan, K. B. Chalasani, A. K. Jain, P. V. Diwan Received November 15, 2002, accepted May 5, 2003 Dr. Prakash V. Diwan, Pharmacology Division, Indian Institute of Chemical Technology, Hyderabad – 500 007 A.P., India [email protected] Pharmazie 58: 807–810 (2003) The virtual insolubility of gliquidone in water results in poor wettability and dissolution characteristics, which may lead to a variation in bioavailability. To improve these characteristics of gliquidone, binary systems with hydroxypropyl-b-cyclodextrin (HP-b-CD) were prepared by classical methods such as physical mixing, kneading, co-evaporation and co-lyophilization. The solid state interaction between the drug and HP-b-CD was assessed by evaluating the binary systems with X-ray diffraction, differen- tial scanning calorimetry and IR- spectroscopy. The results establish the molecular encapsulation and amorphization of gliquidone. The phase solubility profile of gliquidone in aqueous HP-b-CD vehicle À1 resulted in an AL type curve with a stability constant of 1625 M . The dissolution rate of binary sys- tems was greater than that of pure drug and was significantly higher in the case of co-lyophilized and co-evaporated systems. Upon oral administration, [AUC]0-a was significantly higher in case of co-lyo- philized (2 times) and co-evaporated systems (1.5 times) compared to pure drug suspension while other binary systems showed only a marginal improvement. The study ascertained the utility of HP-b- CD in enhancing the oral bioavailability of gliquidone, and points towards a strong influence of the preparation method on the physicochemical properties.
    [Show full text]
  • Sulfonylurea Review
    Human Journals Review Article February 2018 Vol.:11, Issue:3 © All rights are reserved by Farah Yousef et al. Sulfonylurea Review Keywords: Type II diabetes, Sulfonylurea, Glimipiride, Glybu- ride, Structure Activity Relationship. ABSTRACT Farah Yousef*1, Oussama Mansour2, Jehad Herbali3 Diabetes Mellitus is a chronic disease represented with high 1 Ph.D. candidate in pharmaceutical sciences, Damas- glucose blood levels. Although sulfonylurea compounds are the cus University, Damascus, Syria. second preferred drug to treat Type II Diabetes (TYIID), they are still the most used agents due to their lower cost and as a 2 Assistant Professor in pharmaceutical chimestry, Ti- mono-dosing. Literature divides these compounds according to st nd rd shreen University, Lattakia, Syria their discovery into 1 , 2 , 3 generations. However, only six sulfonylurea compounds are now available for use in the United 3 Assistant Professor in pharmaceutical chimestry, Da- States: Chlorpropamide, Glimepiride, Glipizide, Glyburide, mascus University, Damascus, Syria. Tolazamide, and Tolbutamide. They function by increasing Submission: 24 January 2018 insulin secretion from pancreatic beta cells. Their main active site is ATP sensitive potassium ion channels; Kir 6.2\SUR1; Accepted: 29 January 2018 Published: 28 February 2018 Potassium Inward Rectifier ion channel 6.2\ Sulfonylurea re- ceptor 1. They are sulfonamide derivatives. However, research- ers have declared that sulfonylurea moiety is not the only one responsible for this group efficacy. It has been known that sud- den and acute hypoglycemia incidences and weight gain are the www.ijppr.humanjournals.com two most common adverse effects TYIID the patient might face during treatment with sulfonylurea agents. This review indi- cates the historical development of sulfonylurea and the differ- ences among this group members.
    [Show full text]
  • Stems for Nonproprietary Drug Names
    USAN STEM LIST STEM DEFINITION EXAMPLES -abine (see -arabine, -citabine) -ac anti-inflammatory agents (acetic acid derivatives) bromfenac dexpemedolac -acetam (see -racetam) -adol or analgesics (mixed opiate receptor agonists/ tazadolene -adol- antagonists) spiradolene levonantradol -adox antibacterials (quinoline dioxide derivatives) carbadox -afenone antiarrhythmics (propafenone derivatives) alprafenone diprafenonex -afil PDE5 inhibitors tadalafil -aj- antiarrhythmics (ajmaline derivatives) lorajmine -aldrate antacid aluminum salts magaldrate -algron alpha1 - and alpha2 - adrenoreceptor agonists dabuzalgron -alol combined alpha and beta blockers labetalol medroxalol -amidis antimyloidotics tafamidis -amivir (see -vir) -ampa ionotropic non-NMDA glutamate receptors (AMPA and/or KA receptors) subgroup: -ampanel antagonists becampanel -ampator modulators forampator -anib angiogenesis inhibitors pegaptanib cediranib 1 subgroup: -siranib siRNA bevasiranib -andr- androgens nandrolone -anserin serotonin 5-HT2 receptor antagonists altanserin tropanserin adatanserin -antel anthelmintics (undefined group) carbantel subgroup: -quantel 2-deoxoparaherquamide A derivatives derquantel -antrone antineoplastics; anthraquinone derivatives pixantrone -apsel P-selectin antagonists torapsel -arabine antineoplastics (arabinofuranosyl derivatives) fazarabine fludarabine aril-, -aril, -aril- antiviral (arildone derivatives) pleconaril arildone fosarilate -arit antirheumatics (lobenzarit type) lobenzarit clobuzarit -arol anticoagulants (dicumarol type) dicumarol
    [Show full text]
  • Sulfonylurea Stimulation of Insulin Secretion Peter Proks,1 Frank Reimann,2 Nick Green,1 Fiona Gribble,2 and Frances Ashcroft1
    Sulfonylurea Stimulation of Insulin Secretion Peter Proks,1 Frank Reimann,2 Nick Green,1 Fiona Gribble,2 and Frances Ashcroft1 Sulfonylureas are widely used to treat type 2 diabetes smooth, and skeletal muscle, and some brain neurones. In because they stimulate insulin secretion from pancre- all these tissues, opening of KATP channels in response to atic ␤-cells. They primarily act by binding to the SUR metabolic stress leads to inhibition of electrical activity. subunit of the ATP-sensitive potassium (KATP) channel Thus they are involved in the response to both cardiac and and inducing channel closure. However, the channel is cerebral ischemia (2). They are also important in neuronal still able to open to a limited extent when the drug is regulation of glucose homeostasis (3), seizure protection bound, so that high-affinity sulfonylurea inhibition is not complete, even at saturating drug concentrations. (4), and the control of vascular smooth muscle tone (and, thereby, blood pressure) (5). KATP channels are also found in cardiac, skeletal, and smooth muscle, but in these tissues are composed of The KATP channel is a hetero-octameric complex of two different SUR subunits that confer different drug different types of protein subunits: an inwardly rectifying sensitivities. Thus tolbutamide and gliclazide block Kϩ channel, Kir6.x, and a sulfonylurea receptor, SUR (6,7). ␤ ϩ channels containing SUR1 ( -cell type), but not SUR2 Kir6.x belongs to the family of inwardly rectifying K (cardiac, smooth muscle types), whereas glibenclamide, (Kir) channels and assembles as a tetramer to form the glimepiride, repaglinide, and meglitinide block both types of channels.
    [Show full text]
  • Pharmacokinetic and Pharmacodynamic Modeling of Oral
    Liu et al. BMC Pharmacology and Toxicology (2017) 18:54 DOI 10.1186/s40360-017-0161-6 RESEARCH ARTICLE Open Access Pharmacokinetic and pharmacodynamic modeling of oral mitiglinide on glucose lowering in healthy Chinese volunteers Shijia Liu1, Peidong Chen2, Yang Zhao3, Guoliang Dai1, Bingting Sun2, Yao Wang1, Anwei Ding2 and Wenzheng Ju1* Abstract Background: Mitiglinide is a widely used agent for diabetic treatment. We established a pharmacokinetic- pharmacodynamic (PK-PD) model to illustrate the relationship between mitiglinide plasma concentration and its glucose lowering effects in healthy volunteers. Methods: The volunteers participated in the test after the administration of a single dose of 10 mg mitiglinide. The drug concentration in Plasma and the values of glucose levels were determined by LC-MS/MS assay and hexokinase method. A PK-PD model was established with a series of equations to describe the relationship between plasma medicine and glucose, and the equations were solved numerically and fitted to the data with the Phoenix NLME software. Results: The results of the two-compartment model analysis were based on the maximum likelihood criterion and visual inspection of the fittings. The terminal elimination half-life (t1/2) was 1.69 ± 0.16 h and the CL/F was 7.80 ± 1.84 L/h. The plasma glucose levels began to decline by 0.2 h, and hit its bottom decreasing values of 2.6 mg/L at 0.5 h after administration. The calculated parameter and fitting curve indicated that the model established in our experiment fitted well. Conclusions: A PK/PD model illustrates that the relationship between mitiglinide concentration in plasma and glucose lowering effect in healthy volunteers was established.
    [Show full text]
  • Jp Xvii the Japanese Pharmacopoeia
    JP XVII THE JAPANESE PHARMACOPOEIA SEVENTEENTH EDITION Official from April 1, 2016 English Version THE MINISTRY OF HEALTH, LABOUR AND WELFARE Notice: This English Version of the Japanese Pharmacopoeia is published for the convenience of users unfamiliar with the Japanese language. When and if any discrepancy arises between the Japanese original and its English translation, the former is authentic. The Ministry of Health, Labour and Welfare Ministerial Notification No. 64 Pursuant to Paragraph 1, Article 41 of the Law on Securing Quality, Efficacy and Safety of Products including Pharmaceuticals and Medical Devices (Law No. 145, 1960), the Japanese Pharmacopoeia (Ministerial Notification No. 65, 2011), which has been established as follows*, shall be applied on April 1, 2016. However, in the case of drugs which are listed in the Pharmacopoeia (hereinafter referred to as ``previ- ous Pharmacopoeia'') [limited to those listed in the Japanese Pharmacopoeia whose standards are changed in accordance with this notification (hereinafter referred to as ``new Pharmacopoeia'')] and have been approved as of April 1, 2016 as prescribed under Paragraph 1, Article 14 of the same law [including drugs the Minister of Health, Labour and Welfare specifies (the Ministry of Health and Welfare Ministerial Notification No. 104, 1994) as of March 31, 2016 as those exempted from marketing approval pursuant to Paragraph 1, Article 14 of the Same Law (hereinafter referred to as ``drugs exempted from approval'')], the Name and Standards established in the previous Pharmacopoeia (limited to part of the Name and Standards for the drugs concerned) may be accepted to conform to the Name and Standards established in the new Pharmacopoeia before and on September 30, 2017.
    [Show full text]
  • International Journal of Pharmacy Teaching & Practices (IJPTP)
    Vol 5, Issue 3 Supplement 2014 International Journal of Pharmacy Teaching & Practices (IJPTP) Clinical Case Reports - September, 2014 Published by: DRUNPP Association of Sarajevo, Bosnia & Herzegovinia www.iomcworld.com/ijptp email: [email protected] ISSN: 1986-8111 International Journal of Pharmacy Teaching & Practices, Vol5, issue3, Supplement I, 1020-1552. EDITORIAL BOARD Editor-in-Chief Dr. Syed Wasif Gillani Associate Prof. Dr. Azmi Sarriff Editorial Assistant Dr. Mostafa Nejati Executive Editors Prof. Dr. Syed Azhar Syed Sulaiman Dr. Waffa Mohamed El-Anor Ahmed Rashed Prof. Dr. Mark Raymond Mr. Robert Hougland Advisory Board Members Dr. Mensurak Kudumovic Dr. Jasmin Musanovic Dr. Monica Gaidhane Assoc.Prof. Dr. Mok.T Chong Dr. Syed Tajuddin Syed Hassan Dr. Sumeet Dwivedi Dr. Dibyajyoti saha EDITORIAL ADDRESS: KA311, KEYANGANG, BANDAR SUNWAY, SELANGOR, MALAYSIA PUBLISHED BY: DRUNPP, SARAJEVO, BOLNICKA BB. VOLUME 5, ISSUE 3, SUPP I, 2014 ISSN: 1986-8111, INDEXED ON: EBSCO PUBLISHING (EP)USA, INDEX COPERNICUS (IC) POLAND 1020 International Journal of Pharmacy Teaching & Practices, Vol5, issue3, Supplement I, 1020-1552. Table of Contents 1. ISCHIALGIA AND LUNG TUMOR IN MINTOHARDJO HOSPITAL ............................................................ 1026 2. THE MONITORING OF DRUG THERAPY FOR CRF (Chronic Renal Failure) PATIENT IN Dr. MINTOHARDJO, INDONESIAN NAVY MILITARY HOSPITAL.............................................................................................. 1031 3. DIABETES MELLITUS TYPE II, and CHRONIC RENAL FAILURE
    [Show full text]
  • Patent Application Publication ( 10 ) Pub . No . : US 2019 / 0192440 A1
    US 20190192440A1 (19 ) United States (12 ) Patent Application Publication ( 10) Pub . No. : US 2019 /0192440 A1 LI (43 ) Pub . Date : Jun . 27 , 2019 ( 54 ) ORAL DRUG DOSAGE FORM COMPRISING Publication Classification DRUG IN THE FORM OF NANOPARTICLES (51 ) Int . CI. A61K 9 / 20 (2006 .01 ) ( 71 ) Applicant: Triastek , Inc. , Nanjing ( CN ) A61K 9 /00 ( 2006 . 01) A61K 31/ 192 ( 2006 .01 ) (72 ) Inventor : Xiaoling LI , Dublin , CA (US ) A61K 9 / 24 ( 2006 .01 ) ( 52 ) U . S . CI. ( 21 ) Appl. No. : 16 /289 ,499 CPC . .. .. A61K 9 /2031 (2013 . 01 ) ; A61K 9 /0065 ( 22 ) Filed : Feb . 28 , 2019 (2013 .01 ) ; A61K 9 / 209 ( 2013 .01 ) ; A61K 9 /2027 ( 2013 .01 ) ; A61K 31/ 192 ( 2013. 01 ) ; Related U . S . Application Data A61K 9 /2072 ( 2013 .01 ) (63 ) Continuation of application No. 16 /028 ,305 , filed on Jul. 5 , 2018 , now Pat . No . 10 , 258 ,575 , which is a (57 ) ABSTRACT continuation of application No . 15 / 173 ,596 , filed on The present disclosure provides a stable solid pharmaceuti Jun . 3 , 2016 . cal dosage form for oral administration . The dosage form (60 ) Provisional application No . 62 /313 ,092 , filed on Mar. includes a substrate that forms at least one compartment and 24 , 2016 , provisional application No . 62 / 296 , 087 , a drug content loaded into the compartment. The dosage filed on Feb . 17 , 2016 , provisional application No . form is so designed that the active pharmaceutical ingredient 62 / 170, 645 , filed on Jun . 3 , 2015 . of the drug content is released in a controlled manner. Patent Application Publication Jun . 27 , 2019 Sheet 1 of 20 US 2019 /0192440 A1 FIG .
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2015/0202317 A1 Rau Et Al
    US 20150202317A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2015/0202317 A1 Rau et al. (43) Pub. Date: Jul. 23, 2015 (54) DIPEPTDE-BASED PRODRUG LINKERS Publication Classification FOR ALPHATIC AMNE-CONTAINING DRUGS (51) Int. Cl. A647/48 (2006.01) (71) Applicant: Ascendis Pharma A/S, Hellerup (DK) A638/26 (2006.01) A6M5/9 (2006.01) (72) Inventors: Harald Rau, Heidelberg (DE); Torben A 6LX3/553 (2006.01) Le?mann, Neustadt an der Weinstrasse (52) U.S. Cl. (DE) CPC ......... A61K 47/48338 (2013.01); A61 K3I/553 (2013.01); A61 K38/26 (2013.01); A61 K (21) Appl. No.: 14/674,928 47/48215 (2013.01); A61M 5/19 (2013.01) (22) Filed: Mar. 31, 2015 (57) ABSTRACT The present invention relates to a prodrug or a pharmaceuti Related U.S. Application Data cally acceptable salt thereof, comprising a drug linker conju (63) Continuation of application No. 13/574,092, filed on gate D-L, wherein D being a biologically active moiety con Oct. 15, 2012, filed as application No. PCT/EP2011/ taining an aliphatic amine group is conjugated to one or more 050821 on Jan. 21, 2011. polymeric carriers via dipeptide-containing linkers L. Such carrier-linked prodrugs achieve drug releases with therapeu (30) Foreign Application Priority Data tically useful half-lives. The invention also relates to pharma ceutical compositions comprising said prodrugs and their use Jan. 22, 2010 (EP) ................................ 10 151564.1 as medicaments. US 2015/0202317 A1 Jul. 23, 2015 DIPEPTDE-BASED PRODRUG LINKERS 0007 Alternatively, the drugs may be conjugated to a car FOR ALPHATIC AMNE-CONTAINING rier through permanent covalent bonds.
    [Show full text]
  • Pharmaceuticals As Environmental Contaminants
    PharmaceuticalsPharmaceuticals asas EnvironmentalEnvironmental Contaminants:Contaminants: anan OverviewOverview ofof thethe ScienceScience Christian G. Daughton, Ph.D. Chief, Environmental Chemistry Branch Environmental Sciences Division National Exposure Research Laboratory Office of Research and Development Environmental Protection Agency Las Vegas, Nevada 89119 [email protected] Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada Why and how do drugs contaminate the environment? What might it all mean? How do we prevent it? Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada This talk presents only a cursory overview of some of the many science issues surrounding the topic of pharmaceuticals as environmental contaminants Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada A Clarification We sometimes loosely (but incorrectly) refer to drugs, medicines, medications, or pharmaceuticals as being the substances that contaminant the environment. The actual environmental contaminants, however, are the active pharmaceutical ingredients – APIs. These terms are all often used interchangeably Office of Research and Development National Exposure Research Laboratory, Environmental Sciences Division, Las Vegas, Nevada Office of Research and Development Available: http://www.epa.gov/nerlesd1/chemistry/pharma/image/drawing.pdfNational
    [Show full text]