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1-(4-Amino-Cyclohexyl)
(19) & (11) EP 1 598 339 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 211/04 (2006.01) C07D 211/06 (2006.01) 24.06.2009 Bulletin 2009/26 C07D 235/24 (2006.01) C07D 413/04 (2006.01) C07D 235/26 (2006.01) C07D 401/04 (2006.01) (2006.01) (2006.01) (21) Application number: 05014116.7 C07D 401/06 C07D 403/04 C07D 403/06 (2006.01) A61K 31/44 (2006.01) A61K 31/48 (2006.01) A61K 31/415 (2006.01) (22) Date of filing: 18.04.2002 A61K 31/445 (2006.01) A61P 25/04 (2006.01) (54) 1-(4-AMINO-CYCLOHEXYL)-1,3-DIHYDRO-2H-BENZIMIDAZOLE-2-ONE DERIVATIVES AND RELATED COMPOUNDS AS NOCICEPTIN ANALOGS AND ORL1 LIGANDS FOR THE TREATMENT OF PAIN 1-(4-AMINO-CYCLOHEXYL)-1,3-DIHYDRO-2H-BENZIMIDAZOLE-2-ON DERIVATE UND VERWANDTE VERBINDUNGEN ALS NOCICEPTIN ANALOGE UND ORL1 LIGANDEN ZUR BEHANDLUNG VON SCHMERZ DERIVÉS DE LA 1-(4-AMINO-CYCLOHEXYL)-1,3-DIHYDRO-2H-BENZIMIDAZOLE-2-ONE ET COMPOSÉS SIMILAIRES POUR L’UTILISATION COMME ANALOGUES DU NOCICEPTIN ET LIGANDES DU ORL1 POUR LE TRAITEMENT DE LA DOULEUR (84) Designated Contracting States: • Victory, Sam AT BE CH CY DE DK ES FI FR GB GR IE IT LI LU Oak Ridge, NC 27310 (US) MC NL PT SE TR • Whitehead, John Designated Extension States: Newtown, PA 18940 (US) AL LT LV MK RO SI (74) Representative: Maiwald, Walter (30) Priority: 18.04.2001 US 284666 P Maiwald Patentanwalts GmbH 18.04.2001 US 284667 P Elisenhof 18.04.2001 US 284668 P Elisenstrasse 3 18.04.2001 US 284669 P 80335 München (DE) (43) Date of publication of application: (56) References cited: 23.11.2005 Bulletin 2005/47 EP-A- 0 636 614 EP-A- 0 990 653 EP-A- 1 142 587 WO-A-00/06545 (62) Document number(s) of the earlier application(s) in WO-A-00/08013 WO-A-01/05770 accordance with Art. -
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 -
Computational Drug Target Screening Through Protein Interaction Profiles
www.nature.com/scientificreports OPEN Computational Drug Target Screening through Protein Interaction Profiles Received: 27 June 2016 Santiago Vilar1,2, Elías Quezada3, Eugenio Uriarte2, Stefano Costanzi4, Fernanda Borges3, Accepted: 24 October 2016 Dolores Viña5 & George Hripcsak1 Published: 15 November 2016 The development of computational methods to discover novel drug-target interactions on a large scale is of great interest. We propose a new method for virtual screening based on protein interaction profile similarity to discover new targets for molecules, including existing drugs. We calculated Target Interaction Profile Fingerprints (TIPFs) based on ChEMBL database to evaluate drug similarity and generated new putative compound-target candidates from the non-intersecting targets in each pair of compounds. A set of drugs was further studied in monoamine oxidase B (MAO-B) and cyclooxygenase-1 (COX-1) enzyme through molecular docking and experimental assays. The drug ethoxzolamide and the natural compound piperlongumine, present in Piper longum L, showed hMAO-B activity with IC50 values of 25 and 65 μM respectively. Five candidates, including lapatinib, SB-202190, RO-316233, GW786460X and indirubin-3′-monoxime were tested against human COX-1. Compounds SB-202190 and RO-316233 showed a IC50 in hCOX-1 of 24 and 25 μM respectively (similar range as potent inhibitors such as diclofenac and indomethacin in the same experimental conditions). Lapatinib and indirubin- 3′-monoxime showed moderate hCOX-1 activity (19.5% and 28% of enzyme inhibition at 25 μM respectively). Our modeling constitutes a multi-target predictor for large scale virtual screening with potential in lead discovery, repositioning and drug safety. Discovery of new targets for molecules is of great interest in drug design and development1,2. -
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 -
(12) United States Patent (10) Patent No.: US 8,357,723 B2 Satyam (45) Date of Patent: Jan
US008357723B2 (12) United States Patent (10) Patent No.: US 8,357,723 B2 Satyam (45) Date of Patent: Jan. 22, 2013 (54) PRODRUGS CONTAINING NOVEL "Nitric Oxide Donors and Cardiovascular Agents Modulating the BO-CLEAVABLE LINKERS Bioactivity of Nitric Oxide: An Overview” by Louis J. Ignarro, et al., Circulation Research, vol. 90, No. 1, pp. 21-22 (Jan. 11, 002). (75) Inventor: Apparao Satyam, Mumbai (IN) “Bis3-(4-substituted phenyl)prop-2-enedisulfides as a new class of (73) Assignee: Piramal Enterprises Limited and antihyperlipidemic compounds' by Meenakshi Sharma, et al., Apparao Satyam, Mumbai (IN) Bioorganic and Medicinal Chemistry Leters, vol. 14, No. 21, pp. (*) Notice: Subject to any disclaimer, the term of this 5347-5350 (Nov. 1, 2004). patent is extended or adjusted under 35 Abstract Only "Spectrophotometric determination of binary mix U.S.C. 154(b) by 0 days. tures of pseudoephedrine with some histamine H1-receptor antago nists using derivative radio spectrum method' by H. Mahgouh, et al., (21) Appl. No.: 12/977,929 J. Pham Biomed Anal, vol. 31, No. 4, pp. 801-809 Mar. 26, 2003. (22) Filed: Dec. 23, 2010 Peter D. Senter et al., Development of Drug-Release Strategy Based (65) Prior Publication Data on the Reductive Fragmentation pf Benzyl Carbamate Disulfides. Journal of Organic Chemistry, 1990, 55, 2975-2978. Published by US 2011 FO269709 A1 Nov. 3, 2011 American Chemical Society (USA). Related U.S. Application Data Vivekananda M. Virudhula et al., Reductively Activated Disulfide Prodrugs of Paclitaxel. Biorganic & Medicinal Chemistry Letters, (62) Division of application No. 1 1/213,396, filed on Aug. -
Pharmaceutical Appendix to the Tariff Schedule 2
Harmonized Tariff Schedule of the United States (2007) (Rev. 2) Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2007) (Rev. 2) 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. ABACAVIR 136470-78-5 ACIDUM LIDADRONICUM 63132-38-7 ABAFUNGIN 129639-79-8 ACIDUM SALCAPROZICUM 183990-46-7 ABAMECTIN 65195-55-3 ACIDUM SALCLOBUZICUM 387825-03-8 ABANOQUIL 90402-40-7 ACIFRAN 72420-38-3 ABAPERIDONUM 183849-43-6 ACIPIMOX 51037-30-0 ABARELIX 183552-38-7 ACITAZANOLAST 114607-46-4 ABATACEPTUM 332348-12-6 ACITEMATE 101197-99-3 ABCIXIMAB 143653-53-6 ACITRETIN 55079-83-9 ABECARNIL 111841-85-1 ACIVICIN 42228-92-2 ABETIMUSUM 167362-48-3 ACLANTATE 39633-62-0 ABIRATERONE 154229-19-3 ACLARUBICIN 57576-44-0 ABITESARTAN 137882-98-5 ACLATONIUM NAPADISILATE 55077-30-0 ABLUKAST 96566-25-5 ACODAZOLE 79152-85-5 ABRINEURINUM 178535-93-8 ACOLBIFENUM 182167-02-8 ABUNIDAZOLE 91017-58-2 ACONIAZIDE 13410-86-1 ACADESINE 2627-69-2 ACOTIAMIDUM 185106-16-5 ACAMPROSATE 77337-76-9 -
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 -
Interaction of Benzodiazepines with Central Nervous Glycine Receptors: Possible Mechanism of Action (Strychnine Binding/Behavioral Tests) ANNE B
Proc. Nat. Acad. Sci. USA Vol. 71, No. 6, pp. 2246-2250, June 1974 Interaction of Benzodiazepines with Central Nervous Glycine Receptors: Possible Mechanism of Action (strychnine binding/behavioral tests) ANNE B. YOUNG, STEPHEN R. ZUKIN, AND SOLOMON H. SNYDER* Departments of Pharmacology and Experimental Therapeutics and Psychiatry and the Behavioral Sciences, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205 Communicaed by Cheves Walling, January 29, 1974 ABSTRACT Interaction of 21 benzodiazepines with the ously (4). The specific activity of the labeled strychnine was glycine receptor in the brainstem and spinal cord of rat have been evaluated in terms of their displacement of 13 Ci/mmol, with concentrations determined by comparison ['HIstrychnine binding. The rank order of potency of the with the ultraviolet absorption of standard solutions at 254 21 drugs in displacing specific ['H1strychnine binding cor- nm. relates (p < 0.005) with their rank order of potency in a variety of pharmacological and behavioral tests in Tissue Preparation. Male Sprague-Dawley rats (100-150 g) humans and animals that predict clinical efficacy. There were decapitated and the brainstems and spinal cords re- is a 50-fold variation in potency of the series of benzo- moved. Crude synaptic membrane fractions of these tissues diazepines with mean effective dose (ED5.) values ranging were prepared by the differential centrifugation technique from 19juM to >1000 pM. Diazepam (Valium®) and chlor- diazepoxide (Librium®) have EDN's of 26 MM and 200 pM, previously reported (4). respectively, whereas the ED5. for glycine is 25 ;M. The in- hibitory effects of 10 of the agents in two other central ner- Binding A8say. -
Antiepileptic Drugs: Evolution of Our Knowledge and Changes in Drug Trials
ILAE 110th anniversary review paper* Epileptic Disord 2019; 21 (4): 319-29 Antiepileptic drugs: evolution of our knowledge and changes in drug trials Emilio Perucca Past President of the International League Against Epilepsy Division of Clinical and Experimental Pharmacology, Department of Internal Medicine and Therapeutics, University of Pavia, Pavia and IRCCS Mondino Foundation, Pavia, Italy Received April 30, 2019; Accepted June 01, 2019 ABSTRACT – Clinical trials provide the evidence needed for rational use of medicines. The evolution of drug trials follows largely the evolution of regulatory requirements. This article summarizes methodological changes in antiepileptic drug trials and associated advances in knowledge starting from 1938, the year phenytoin was introduced and also the year when evi- dence of safety was made a requirement for the marketing of medicines in the United States. The first period (1938-1969) saw the introduction of over 20 new drugs for epilepsy, many of which did not withstand the test of time. Only few well controlled trials were completed in that period and trial designs were generally suboptimal due to methodological constraints. The intermediate period (1970-1988) did not see the introduction of any major new medication, but important therapeutic advances took place due to improved understanding of the properties of available drugs. The value of therapeutic drug monitoring and monotherapy were recognized dur- ing the intermediate period, which also saw major improvements in trial methodology. The last period (1989-2019) was dominated by the introduc- tion of second-generation drugs, and further evolution in the design of monotherapy and adjunctive-therapy trials. The expansion of the pharma- cological armamentarium has improved opportunities for tailoring drug treatment to the characteristics of the individual. -
Therapeutic Applications of the Carbonic Anhydrase Inhibitors
REVIEW Therapeutic applications of the carbonic anhydrase inhibitors Claudiu T Supuran Inhibitors of the zinc enzyme carbonic anhydrase (CA) targeting different isozymes among Università degli Studi, Laboratorio di Chimica the 15 presently reported in humans have various therapeutic applications. These enzymes Bioinorganica, Rm 188, are efficient catalysts for the hydration of carbon dioxide to bicarbonate and protons, Via della Lastruccia 3, playing crucial physiological/pathological roles related to acid–base homeostasis, secretion I-50019 Sesto Fiorentino (Firenze), Italy of electrolytes, transport of ions, biosynthetic reactions and tumorigenesis. Many CA Tel.: +39 055 457 3005; inhibitors have been reported as antiglaucoma, anticancer and antiobesity agents, or for Fax: +39 055 457 3385; the management of a variety of neurological disorders, including epilepsy and altitude E-mail: claudiu.supuran@ unifi.it disease. Furthermore, some CA isozymes appear to be valuable markers of tumor progression in a variety of tissues/organs. Various CAs present in pathogens such as Plasmodium falciparum, Helicobacter pylori, Mycobacterium tuberculosis, Candida albicans and Cryptococcus neoformans, have started to also be investigated recently as drug targets. Recent progress in all these areas, as well as in the characterization of new such enzymes isolated in many other organisms/tissues, in addition to their detailed catalytic/inhibition mechanisms, are reviewed herein, together with the therapeutic use of these enzyme inhibitors and drug-design studies for obtaining such new-generation derivatives with improved activity. Among the zinc enzymes extensively studied, forms (CA VA and CA VB), as well as a the carbonic anhydrases (CAs) occupy a special secreted CA isozyme (in saliva and milk; place for several reasons. -
P=.004), Comparable. Median Post-LT VPA-ALF Contraindicated for Acute
and 76% were due to neurocysticercosis. (Arya R, Gulati S, Kabra M, Sahu JK, Kalra V. Folic acid supplementation prevents phenytoin-induced gingival overgrowth in children. Neurology April 12, 2011;76:1338-1343). (Response and reprints: Dr Sheffali Gulati, Department of Pediatrics, AIIMS, Ansari Nagar, New Delhi, 110 029, India. E-mail: [email protected] COMMENT. Gingival hyperplasia associated with phenytoin treatment of epilepsy is reported in as few as 3% of cases (Lennox WG, 1940) to as many as 78% (Gardner AF et al, 1962). It occurs more frequently in children than in adults. Numerous mechanisms have been proposed but few of proven significance. Other hydantoin anticonvulsants (mephenytoin, ethotoin, and albutoin) cause little or no gingival hyperplasia. The above investigators have discovered an important and correctable factor in the mechanism in their clinic population. The authors allude to a lack of dental hygiene in a high proportion of patients, a known contributing factor associated with tissue inflammation and irritation. Hyperplasia does not occur in edentulous adults. Phenytoin has an affinity for gingival tissue, and its effect on collagen and keratin in connective tissue has been used in the promotion of healing of wounds and leg ulcers (Shafer WG et al, 1958; Houck JC et al, 1972). In addition to man, only the ferret is susceptible to phenytoin gum hyperplasia, an interesting companion in science. Mechanisms largely disproven include a deficiency of ascorbic acid, adrenocortical dysfunction, and allergy (Gardner, 1962). Hyperglycemia induced by phenytoin, an effect discovered in our neurology research laboratories at Children's Memorial Hospital (Belton NR et al. -
Identifying Nootropic Drug Targets Via Large-Scale Cognitive GWAS and Transcriptomics
bioRxiv preprint doi: https://doi.org/10.1101/2020.02.06.934752; this version posted February 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. Title: Identifying Nootropic Drug Targets via Large-Scale Cognitive GWAS and Transcriptomics Max Lam1, 2, 3,4, Chia-Yen, Chen3,5,6, Xia Yan7,8, W. David Hill9, 10, Joey W. Trampush11, Jin Yu1, Emma Knowles12,13,14, Gail Davies9, 10, Eli Stahl15, 16, Laura Huckins15, 16, David C. Liewald10, Srdjan Djurovic17, 18, Ingrid Melle18, 19, Andrea Christoforou20, Ivar Reinvang21, Pamela DeRosse1, 22, 23, Astri J. Lundervold24, Vidar M. Steen18, 20, Thomas Espeseth19, 21, Katri Räikkönen25, Elisabeth Widen26, Aarno Palotie26, 27, 28, Johan G. Eriksson29, 30, 31, Ina Giegling32, Bettina Konte32, Annette M. Hartmann32, Panos Roussos15, 16, 33, Stella Giakoumaki34, Katherine E. Burdick15, 33, 35, Antony Payton36, William Ollier37, 38, Ornit Chiba- Falek39, Deborah K. Koltai39, 40 , Anna C. Need41, Elizabeth T. Cirulli42, Aristotle N. Voineskos43, Nikos C. Stefanis44, 45, 46, Dimitrios Avramopoulos47, 48, Alex Hatzimanolis44, 45, 46, Nikolaos Smyrnis44, 45, Robert M. Bilder49, Nelson A. Freimer49, Tyrone D. Cannon50, 51, Edythe London49, Russell A. Poldrack52, Fred W. Sabb53, Eliza Congdon49, Emily Drabant Conley54, Matthew A. Scult55, Dwight Dickinson56, Richard E. Straub57, Gary Donohoe58, Derek Morris58, Aiden Corvin59, Michael Gill59, Ahmad R. Hariri55, Daniel R. Weinberger57, Neil Pendleton60, Panos Bitsios61, Dan Rujescu32, Jari Lahti25, 62, Stephanie Le Hellard18, 20, Matthew C.