DOCSLIB.ORG

Identification and Analysis of Hepatitis C Virus NS3 Helicase Inhibitors Using Nucleic Acid Binding Assays

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Identification and Analysis of Hepatitis C Virus NS3 Helicase Inhibitors Using Nucleic Acid Binding Assays SUPPLEMENTAL INFORMATION Identification and Analysis of Hepatitis C virus NS3 Helicase Inhibitors Using Nucleic Acid Binding Assays Sourav Mukherjee,1 Alicia M. Hanson,1 William R. Shadrick,1 Jean Ndjomou,1 Noreena L. Sweeney,1 John J. Hernandez,1 Diana Bartczak,1 Kelin Li,2 Kevin J. Frankowski,2 Julie A. Heck,3,4 Leggy A. Arnold,1 Frank J. Schoenen,3 and David N. Frick1,* 1Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI, 53211, USA. 2University of Kansas Specialized Chemistry Center, University of Kansas, 2034 Becker Dr., Lawrence, KS 66047. 3Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY, 10595. Table S1: Compound effects on the fluorescent polarization (FP)-based NS3h-DNA binding assay and the molecular beacon based helicase assay (MBHAs). Means ± standard deviations (n=2) are reported for normalized inhibition (%) and assay interference (ratio). Compounds colored blue are primuline derivatives, green compounds are known DNA binding agents, and pink compounds are other disclosed NS3 helicase inhibitors. [Data relate to Fig. 4] Table S2: Results of a screen of Sigma’s LOPAC for inhibitors of Cy5-dT15-NS3h complex formation. Pink compounds inhibited complex formation more than 60%, and green compounds interfered with the assay more than 20%. [Data relate to Fig. 5] Table S3: The Cy-15-dT15-SSB binding assay as a screen for specific HCV helicase inhibitors. Means ± standard deviations of IC50 values obtained in titrations (n=3) with each of the shown primuline derivatives. Compounds are ranked based on their ability to inhibit the formation of the Cy-15-dT15-SSB complex, with the least potent compounds on the top. [Data relate to Fig. 8]! Table&S1 $Cy52dT152NS3h$Binding$ $Cy52dT152NS3h$Binding$ DNA$Unwinding$(MBHA)$ DNA$Unwinding$(MBHA)$ CID$No./Compound$Name$ %$Inhibition Interference$ %Inhibition Interference TO*PRO*3 *63&±&0 1.4&±&0.0 115&±&2 0.5&±&0.0 Hoechst&33258 *96&±&2 0.1&±&0.0 104&±&6 0.3&±&0.0 Chromomycin&A3 *4&±&8 1.0&±&0.0 96&±&1 1.0&±&0.0 4049406 62&±&5 0.7&±&0.0 96&±&2 0.7&±&0.0 53308659 17&±&2 1.1&±&0.1 95&±&0 1.0&±&0.0 SYBR&Green&I 24&±&2 0.8&±&0.0 91&±&3 0.7&±&0.0 53255474 46&±&65 0.3&±&0.2 90&±&2 0.4&±&0.0 44251438 74&±&17 1.0&±&0.0 89&±&3 0.9&±&0.0 486270 30&±&4 0.6&±&0.0 87&±&4 0.6&±&0.0 53239937 9&±&2 1.0&±&0.0 87&±&5 1.0&±&0.0 44251434 47&±&10 1.0&±&0.0 82&±&4 1.0&±&0.0 44251428 54&±&4 1.0&±&0.0 81&±&12 1.0&±&0.0 247520 *17&±&2 0.8&±&0.0 80&±&4 0.7&±&0.0 3413238 63&±&2 0.7&±&0.0 78&±&7 0.7&±&0.0 49849282 22&±&3 1.0&±&0.0 77&±&8 1.0&±&0.0 Titan&Yellow 97&±&4 1.1&±&0.0 75&±&3 1.0&±&0.0 483665 *21&±&2 0.9&±&0.0 74&±&4 0.8&±&0.0 4176595 *13&±&3 0.8&±&0.0 69&±&2 0.9&±&0.0 4111820 4&±&2 0.7&±&0.0 68&±&7 0.9&±&0.0 7080057 *17&±&0 0.9&±&0.0 67&±&1 0.9&±&0.0 49849300 73&±&0 1.0&±&0.0 63&±&2 1.0&±&0.0 Soluble&Blue&HT 78&±&0 1.0&±&0.0 63&±&12 0.8&±&0.0 52939982 *9&±&2 0.9&±&0.0 59&±&4 1.0&±&0.0 44251431 73&±&8 1.0&±&0.0 58&±&23 1.0&±&0.0 Ellipticine *6&±&0 1.0&±&0.0 57&±&4 0.6&±&0.0 49849299 *2&±&1 1.0&±&0.0 53&±&14 1.0&±&0.0 Netropsin 8&±&1 0.9&±&0.0 51&±&20 0.8&±&0.1 Thiazole&Orange *4&±&1 0.9&±&0.0 49&±&7 0.7&±&0.0 50930741 56&±&13 1.0&±&0.0 46&±&5 1.0&±&0.0 50930749 *1&±&5 1.0&±&0.0 41&±&13 1.0&±&0.0 50930730 46&±&30 1.0&±&0.0 41&±&25 1.0&±&0.0 49849293 39&±&2 1.0&±&0.0 32&±&12 0.9&±&0.0 49849293 20&±&6 1.0&±&0.0 31&±&4 0.9&±&0.0 50930737 58&±&14 1.0&±&0.0 31&±&11 1.0&±&0.0 50930733 22&±&6 1.0&±&0.0 29&±&4 1.0&±&0.0 50930738 91&±&1 1.1&±&0.0 28&±&2 1.0&±&0.0 DAPI 4&±&0 0.9&±&0.0 28&±&9 0.8&±&0.0 Rebeccamycin *10&±&2 1.0&±&0.0 27&±&11 0.8&±&0.1 46913723 *10&±&4 1.0&±&0.0 27&±&3 0.9&±&0.0 Proflavin *4&±&1 0.9&±&0.0 27&±&4 0.8&±&0.0 53308658 30&±&14 0.9&±&0.2 27&±&2 1.0&±&0.0 50930755 18&±&3 1.0&±&0.0 26&±&1 0.9&±&0.0 49849287 19&±&5 1.0&±&0.0 25&±&1 0.9&±&0.0 Quinacrine *5&±&4 0.9&±&0.0 25&±&2 0.9&±&0.0 49849302 28&±&1 1.0&±&0.0 24&±&6 0.9&±&0.0 16060752 11&±&5 0.9&±&0.0 24&±&3 0.8&±&0.0 5479184 10&±&3 0.9&±&0.0 24&±&1 0.9&±&0.0 50930751 19&±&6 1.0&±&0.0 23&±&0 1.0&±&0.0 53312458 43&±&6 1.0&±&0.0 23&±&2 0.9&±&0.0 49849298 13&±&1 1.0&±&0.0 22&±&3 0.9&±&0.0 50930740 34&±&6 1.0&±&0.0 22&±&1 1.0&±&0.0 Thioflavin&T *8&±&0 1.0&±&0.0 21&±&2 0.9&±&0.0 3084034 30&±&4 1.0&±&0.0 21&±&12 0.8&±&0.0 Eva&Green *3&±&4 1.0&±&0.0 20&±&2 0.9&±&0.0 53255447 18&±&7 1.0&±&0.0 20&±&0 0.9&±&0.1 52914816 10&±&2 1.0&±&0.0 20&±&9 1.0&±&0.0 50930745 11&±&6 1.0&±&0.0 19&±&6 0.9&±&0.0 Berenil *46&±&0 1.0&±&0.0 19&±&3 0.9&±&0.0 49849280 41&±&0 1.0&±&0.0 17&±&3 0.9&±&0.0 46202556 *8&±&0 1.0&±&0.0 17&±&1 1.0&±&0.0 50930743 38&±&2 1.0&±&0.0 17&±&5 0.9&±&0.0 49849276 28&±&11 1.0&±&0.0 16&±&5 1.0&±&0.0 50930732 4&±&0 1.0&±&0.0 16&±&8 1.0&±&0.0 50930756 52&±&10 1.0&±&0.0 15&±&2 1.0&±&0.0 9585555 *4&±&2 0.9&±&0.0 15&±&5 1.0&±&0.0 3832647 *6&±&2 1.0&±&0.0 15&±&2 1.0&±&0.0 Trioxsalen *6&±&2 1.0&±&0.0 15&±&6 0.9&±&0.0 Carrier&Blank/DMSO *7&±&2 1.0&±&0.0 8&±&4 1.0&±&0.0 50930734 18&±&4 1.1&±&0.0 14&±&6 1.0&±&0.0 49849284 26&±&8 1.0&±&0.0 14&±&7 1.0&±&0.0 1 Table&S1 $Cy52dT152NS3h$Binding$ $Cy52dT152NS3h$Binding$ DNA$Unwinding$(MBHA)$ DNA$Unwinding$(MBHA)$ CID$No./Compound$Name$ %$Inhibition Interference$ %Inhibition Interference 53255452 13&±&5 1.0&±&0.0 14&±&0 0.9&±&0.0 5362502 *1&±&5 1.0&±&0.0 13&±&3 0.9&±&0.0 Luciferin *4&±&1 1.0&±&0.0 13&±&2 0.9&±&0.0 9682118 *9&±&1 1.0&±&0.0 13&±&4 1.0&±&0.0 3643004 *5&±&1 1.0&±&0.0 12&±&5 1.0&±&0.0 Carrier&Blank/DMSO *8&±&1 1.0&±&0.0 12&±&4 1.0&±&0.0 46916208 *9&±&2 1.0&±&0.0 11&±&4 1.0&±&0.0 5691857 3&±&0 0.9&±&0.0 11&±&4 1.0&±&0.0 4594423 *5&±&1 1.0&±&0.0 11&±&4 1.0&±&0.0 3496625 *5&±&0 1.0&±&0.0 11&±&3 1.0&±&0.0 2998553 *1&±&2 1.0&±&0.0 11&±&9 0.9&±&0.0 6540194 *9&±&0 1.0&±&0.0 10&±&4 1.0&±&0.0 Primulin 31&±&3 1.0&±&0.0 10&±&4 1.0&±&0.0 978069 1&±&1 0.9&±&0.0 10&±&8 1.0&±&0.0 5447034 *3&±&2 1.0&±&0.0 10&±&14 0.9&±&0.1 45382099 *4&±&1 1.0&±&0.0 10&±&2 1.0&±&0.0 6064372 *6&±&3 0.9&±&0.0 10&±&2 1.0&±&0.0 53255449 0&±&1 1.0&±&0.0 10&±&6 1.0&±&0.0 49849286 27&±&5 1.0&±&0.0 10&±&3 1.0&±&0.0 1293387 *7&±&1 0.9&±&0.0 10&±&7 1.0&±&0.0 6540199 *7&±&3 1.0&±&0.0 9&±&5 1.0&±&0.0 7314627 1&±&1 1.0&±&0.0 9&±&6 1.0&±&0.0 5281571 20&±&2 1.0&±&0.0 9&±&5 1.0&±&0.0 45382098 *4&±&3 1.0&±&0.0 9&±&3 1.0&±&0.0 49795072 *8&±&0 1.0&±&0.0 9&±&9 1.0&±&0.0 4473963 *11&±&1 1.0&±&0.0 8&±&2 1.0&±&0.0 44251428 24&±&6 1.0&±&0.0 8&±&2 1.0&±&0.0 16060753 *10&±&4 1.0&±&0.0 8&±&3 1.0&±&0.0 Carrier&Blank/DMSO *8&±&0 1.0&±&0.0 14&±&6 0.9&±&0.0 46916209 *9&±&0 1.0&±&0.0 8&±&5 1.0&±&0.0 49849289 36&±&2 1.0&±&0.0 8&±&6 1.0&±&0.0 5860596 *4&±&0 1.0&±&0.0 8&±&6 1.0&±&0.0 4611776 *5&±&3 1.0&±&0.0 8&±&2 1.0&±&0.0 16060655 *8&±&2 1.0&±&0.0 7&±&4 1.0&±&0.0 50930748 31&±&2 1.0&±&0.0 7&±&1 1.0&±&0.0 46839370 29&±&5 1.0&±&0.0 7&±&3 1.0&±&0.0 5736971 *3&±&2 0.9&±&0.0 7&±&2 1.1&±&0.0 1601813 *5&±&3 1.0&±&0.0 7&±&3 1.0&±&0.0 2186405 *6&±&0 0.9&±&0.0 7&±&11 1.0&±&0.0 6540163 *10&±&1 0.9&±&0.0 7&±&2 1.0&±&0.0 5293297 *7&±&2 0.9&±&0.0 7&±&0 1.0&±&0.0 45382102 *4&±&2 1.0&±&0.0 7&±&3 1.0&±&0.0 50904396 *10&±&1 1.0&±&0.0 6&±&13 1.0&±&0.0 2571817 *8&±&2 1.0&±&0.0 6&±&4 1.0&±&0.0 4371917 *26&±&4 1.0&±&0.0 6&±&6 1.0&±&0.0 2330223 *47&±&0 0.9&±&0.0 6&±&5 1.0&±&0.0 46897855 37&±&2 1.0&±&0.0 5&±&2 1.0&±&0.0 49795071 2&±&2 1.0&±&0.0 5&±&11 1.0&±&0.0 16238633 *4&±&1 1.0&±&0.0 5&±&4 1.0&±&0.0 1959044 *1&±&2 0.9&±&0.0 4&±&1 1.0&±&0.0 4051948 *7&±&1 1.0&±&0.0 4&±&11 1.0&±&0.0 2214934 *4&±&3 0.9&±&0.0 4&±&3 1.0&±&0.0 4872167 *4&±&2 1.0&±&0.0 4&±&5 1.0&±&0.0 49849294 32&±&6 1.0&±&0.0 4&±&5 1.0&±&0.0 45382104 0&±&1 1.0&±&0.0 4&±&3 1.0&±&0.0 49849279 *5&±&6 1.0&±&0.0 4&±&9 1.0&±&0.0 1126404 *8&±&2 1.0&±&0.0 3&±&6 1.0&±&0.0 53255450 12&±&2 1.0&±&0.0 3&±&4 1.0&±&0.0 49849295 8&±&3 1.0&±&0.0 3&±&1 1.0&±&0.0 45382101 *5&±&2 1.0&±&0.0 2&±&2 1.0&±&0.0 53255448 9&±&1 1.0&±&0.0 2&±&6 1.0&±&0.0 24818137 *3&±&2 1.0&±&0.0 1&±&7 1.0&±&0.0 44251427 8&±&2 1.0&±&0.0 0&±&16 1.1&±&0.0 44251433 7&±&3 1.0&±&0.0 0&±&11 1.1&±&0.0 2115891 7&±&2 0.9&±&0.0 *1&±&6 1.1&±&0.0 45382097 *7&±&2 1.0&±&0.0 *1&±&9 1.0&±&0.0 44251429 18&±&0 1.0&±&0.0 *1&±&3 1.1&±&0.0 46839371 *8&±&2 0.9&±&0.0 *1&±&8 1.0&±&0.0 49795073 *9&±&1 1.0&±&0.0 *1&±&0 1.0&±&0.0 45382103 0&±&2 1.0&±&0.0 *2&±&5 1.1&±&0.0 2 Table&S1 $Cy52dT152NS3h$Binding$ $Cy52dT152NS3h$Binding$ DNA$Unwinding$(MBHA)$ DNA$Unwinding$(MBHA)$ CID$No./Compound$Name$ %$Inhibition Interference$ %Inhibition Interference 3923766 *9&±&2 0.9&±&0.0 *2&±&8 1.0&±&0.0 3291242 *1&±&2 0.9&±&0.0 *4&±&14 1.1&±&0.0 3138378 *9&±&0 0.9&±&0.0 *5&±&4 1.0&±&0.0 49849290 1&±&0 1.0&±&0.0 22&±&7 1.0&±&0.0 3 Table&S2 (Cy53dT153NS3h(Binding( (Cy53dT153NS3h(Binding( Compound(Name( Sigma(Cat.(No.
Load more

Recommended publications
  • Synthesis of Conformationally Constrained Glutamate Analogues and Their Preliminary Evaluation As Glutamate Transport Inhibitors
    University of Montana ScholarWorks at University of Montana Graduate Student Theses, Dissertations, & Professional Papers Graduate School 2002 Synthesis of conformationally constrained glutamate analogues and their preliminary evaluation as glutamate transport inhibitors Travis Taylor Denton The University of Montana Follow this and additional works at: https://scholarworks.umt.edu/etd Let us know how access to this document benefits ou.y Recommended Citation Denton, Travis Taylor, "Synthesis of conformationally constrained glutamate analogues and their preliminary evaluation as glutamate transport inhibitors" (2002). Graduate Student Theses, Dissertations, & Professional Papers. 9450. https://scholarworks.umt.edu/etd/9450 This Dissertation is brought to you for free and open access by the Graduate School at ScholarWorks at University of Montana. It has been accepted for inclusion in Graduate Student Theses, Dissertations, & Professional Papers by an authorized administrator of ScholarWorks at University of Montana. For more information, please contact [email protected]. INFORMATION TO USERS This manuscript has been reproduced from the microfilm master. UMI films the text directly from the original or copy submitted. Thus, some thesis and dissertation copies are in typewriter face, while others may be from any type of computer printer. The quality of this reproduction is dependent upon the quality of the copy submitted. Broken or indistinct print, colored or poor quality illustrations and photographs, print bleedthrough, substandard margins, and improper alignment can adversely affect reproduction. In the unlikely event that the author did not send UMI a complete manuscript and there are missing pages, these will be noted. Also, if unauthorized copyright material had to be removed, a note will indicate the deletion.
    [Show full text]
  • (12) Patent Application Publication (10) Pub. No.: US 2004/0224020 A1 Schoenhard (43) Pub
    US 2004O224020A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2004/0224020 A1 Schoenhard (43) Pub. Date: Nov. 11, 2004 (54) ORAL DOSAGE FORMS WITH (22) Filed: Dec. 18, 2003 THERAPEUTICALLY ACTIVE AGENTS IN CONTROLLED RELEASE CORES AND Related U.S. Application Data IMMEDIATE RELEASE GELATIN CAPSULE COATS (60) Provisional application No. 60/434,839, filed on Dec. 18, 2002. (76) Inventor: Grant L. Schoenhard, San Carlos, CA (US) Publication Classification Correspondence Address: (51) Int. Cl. ................................................... A61K 9/24 Janet M. McNicholas (52) U.S. Cl. .............................................................. 424/471 McAndrews, Held & Malloy, Ltd. 34th Floor (57) ABSTRACT 500 W. Madison Street Chicago, IL 60661 (US) The present invention relates to oral dosage form with active agents in controlled release cores and in immediate release (21) Appl. No.: 10/742,672 gelatin capsule coats. Patent Application Publication Nov. 11, 2004 Sheet 1 of 3 US 2004/0224020 A1 r N 2.S Hr s Patent Application Publication Nov. 11, 2004 Sheet 2 of 3 US 2004/0224020 A1 r CN -8 e N va N . t Cd NOLLYRILNONOO Patent Application Publication Nov. 11, 2004 Sheet 3 of 3 US 2004/0224020 A1 US 2004/0224020 A1 Nov. 11, 2004 ORAL DOSAGE FORMS WITH released formulations, a long t is particularly disadvan THERAPEUTICALLY ACTIVE AGENTS IN tageous to patients Seeking urgent treatment and to maintain CONTROLLED RELEASE CORES AND MEC levels. A second difference in the pharmacokinetic IMMEDIATE RELEASE GELATIN CAPSULE profiles of controlled release in comparison to immediate COATS release drug formulations is that the duration of Sustained plasma levels is longer in the controlled release formula CROSS REFERENCED APPLICATIONS tions.
    [Show full text]
  • INVESTIGATION of NATURAL PRODUCT SCAFFOLDS for the DEVELOPMENT of OPIOID RECEPTOR LIGANDS by Katherine M
    INVESTIGATION OF NATURAL PRODUCT SCAFFOLDS FOR THE DEVELOPMENT OF OPIOID RECEPTOR LIGANDS By Katherine M. Prevatt-Smith Submitted to the graduate degree program in Medicinal Chemistry and the Graduate Faculty of the University of Kansas in partial fulfillment of the requirements for the degree of Doctor of Philosophy. _________________________________ Chairperson: Dr. Thomas E. Prisinzano _________________________________ Dr. Brian S. J. Blagg _________________________________ Dr. Michael F. Rafferty _________________________________ Dr. Paul R. Hanson _________________________________ Dr. Susan M. Lunte Date Defended: July 18, 2012 The Dissertation Committee for Katherine M. Prevatt-Smith certifies that this is the approved version of the following dissertation: INVESTIGATION OF NATURAL PRODUCT SCAFFOLDS FOR THE DEVELOPMENT OF OPIOID RECEPTOR LIGANDS _________________________________ Chairperson: Dr. Thomas E. Prisinzano Date approved: July 18, 2012 ii ABSTRACT Kappa opioid (KOP) receptors have been suggested as an alternative target to the mu opioid (MOP) receptor for the treatment of pain because KOP activation is associated with fewer negative side-effects (respiratory depression, constipation, tolerance, and dependence). The KOP receptor has also been implicated in several abuse-related effects in the central nervous system (CNS). KOP ligands have been investigated as pharmacotherapies for drug abuse; KOP agonists have been shown to modulate dopamine concentrations in the CNS as well as attenuate the self-administration of cocaine in a variety of species, and KOP antagonists have potential in the treatment of relapse. One drawback of current opioid ligand investigation is that many compounds are based on the morphine scaffold and thus have similar properties, both positive and negative, to the parent molecule. Thus there is increasing need to discover new chemical scaffolds with opioid receptor activity.
    [Show full text]
  • TABLE 1 Studies of Antagonist Activity in Constitutively Active
    TABLE 1 Studies of antagonist activity in constitutively active receptors systems shown to demonstrate inverse agonism for at least one ligand Targets are natural Gs and constitutively active mutants (CAM) of GPCRs. Of 380 antagonists, 85% of the ligands demonstrate inverse agonism. Receptor Neutral Antagonist Inverse Agonist Reference Human β2-adrenergic Dichloroisoproterenol, pindolol, labetolol, timolol, Chidiac et al., 1996; Azzi et alprenolol, propranolol, ICI 118,551, cyanopindolol al., 2001 Turkey erythrocyte β-adrenergic Propranolol, pindolol Gotze et al., 1994 Human β2-adrenergic (CAM) Propranolol Betaxolol, ICI 118,551, sotalol, timolol Samama et al., 1994; Stevens and Milligan, 1998 Human/guinea pig β1-adrenergic Atenolol, propranolol Mewes et al., 1993 Human β1-adrenergic Carvedilol CGP20712A, metoprolol, bisoprolol Engelhardt et al., 2001 Rat α2D-adrenergic Rauwolscine, yohimbine, WB 4101, idazoxan, Tian et al., 1994 phentolamine, Human α2A-adrenergic Napthazoline, Rauwolscine, idazoxan, altipamezole, levomedetomidine, Jansson et al., 1998; Pauwels MPV-2088 (–)RX811059, RX 831003 et al., 2002 Human α2C-adrenergic RX821002, yohimbine Cayla et al., 1999 Human α2D-adrenergic Prazosin McCune et al., 2000 Rat α2-adrenoceptor MK912 RX821002 Murrin et al., 2000 Porcine α2A adrenoceptor (CAM- Idazoxan Rauwolscine, yohimbine, RX821002, MK912, Wade et al., 2001 T373K) phentolamine Human α2A-adrenoceptor (CAM) Dexefaroxan, (+)RX811059, (–)RX811059, RS15385, yohimbine, Pauwels et al., 2000 atipamezole fluparoxan, WB 4101 Hamster α1B-adrenergic
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 9,498,481 B2 Rao Et Al
    USOO9498481 B2 (12) United States Patent (10) Patent No.: US 9,498,481 B2 Rao et al. (45) Date of Patent: *Nov. 22, 2016 (54) CYCLOPROPYL MODULATORS OF P2Y12 WO WO95/26325 10, 1995 RECEPTOR WO WO99/O5142 2, 1999 WO WOOO/34283 6, 2000 WO WO O1/92262 12/2001 (71) Applicant: Apharaceuticals. Inc., La WO WO O1/922.63 12/2001 olla, CA (US) WO WO 2011/O17108 2, 2011 (72) Inventors: Tadimeti Rao, San Diego, CA (US); Chengzhi Zhang, San Diego, CA (US) OTHER PUBLICATIONS Drugs of the Future 32(10), 845-853 (2007).* (73) Assignee: Auspex Pharmaceuticals, Inc., LaJolla, Tantry et al. in Expert Opin. Invest. Drugs (2007) 16(2):225-229.* CA (US) Wallentin et al. in the New England Journal of Medicine, 361 (11), 1045-1057 (2009).* (*) Notice: Subject to any disclaimer, the term of this Husted et al. in The European Heart Journal 27, 1038-1047 (2006).* patent is extended or adjusted under 35 Auspex in www.businesswire.com/news/home/20081023005201/ U.S.C. 154(b) by Od en/Auspex-Pharmaceuticals-Announces-Positive-Results-Clinical M YW- (b) by ayS. Study (published: Oct. 23, 2008).* This patent is Subject to a terminal dis- Concert In www.concertpharma. com/news/ claimer ConcertPresentsPreclinicalResultsNAMS.htm (published: Sep. 25. 2008).* Concert2 in Expert Rev. Anti Infect. Ther. 6(6), 782 (2008).* (21) Appl. No.: 14/977,056 Springthorpe et al. in Bioorganic & Medicinal Chemistry Letters 17. 6013-6018 (2007).* (22) Filed: Dec. 21, 2015 Leis et al. in Current Organic Chemistry 2, 131-144 (1998).* Angiolillo et al., Pharmacology of emerging novel platelet inhibi (65) Prior Publication Data tors, American Heart Journal, 2008, 156(2) Supp.
    [Show full text]
  • Role of Citicoline in the Management of Traumatic Brain Injury
    pharmaceuticals Review Role of Citicoline in the Management of Traumatic Brain Injury Julio J. Secades Medical Department, Ferrer, 08029 Barcelona, Spain; [email protected] Abstract: Head injury is among the most devastating types of injury, specifically called Traumatic Brain Injury (TBI). There is a need to diminish the morbidity related with TBI and to improve the outcome of patients suffering TBI. Among the improvements in the treatment of TBI, neuroprotection is one of the upcoming improvements. Citicoline has been used in the management of brain ischemia related disorders, such as TBI. Citicoline has biochemical, pharmacological, and pharmacokinetic characteristics that make it a potentially useful neuroprotective drug for the management of TBI. A short review of these characteristics is included in this paper. Moreover, a narrative review of almost all the published or communicated studies performed with this drug in the management of patients with head injury is included. Based on the results obtained in these clinical studies, it is possible to conclude that citicoline is able to accelerate the recovery of consciousness and to improve the outcome of this kind of patient, with an excellent safety profile. Thus, citicoline could have a potential role in the management of TBI. Keywords: CDP-choline; citicoline; pharmacological neuroprotection; brain ischemia; traumatic brain injury; head injury Citation: Secades, J.J. Role of 1. Introduction Citicoline in the Management of Traumatic brain injury (TBI) is among the most devastating types of injury and can Traumatic Brain Injury. result in a different profile of neurological and cognitive deficits, and even death in the most Pharmaceuticals 2021, 14, 410.
    [Show full text]
  • From Inverse Agonism to 'Paradoxical Pharmacology' Richard A
    International Congress Series 1249 (2003) 27-37 From inverse agonism to 'Paradoxical Pharmacology' Richard A. Bond*, Kenda L.J. Evans, Zsirzsanna Callaerts-Vegh Department of Pharmacological and Pharmaceutical Sciences, University of Houston, 521 Science and Research Bldg 2, 4800 Caltioun, Houston, TX 77204-5037, USA Received 16 April 2003; accepted 16 April 2003 Abstract The constitutive or spontaneous activity of G protein-coupled receptors (GPCRs) and compounds acting as inverse agonists is a recent but well-established phenomenon. Dozens of receptor subtypes for numerous neurotransmitters and hormones have been shown to posses this property. However, do to the apparently low percentage of receptors in the spontaneously active state, the physiologic relevance of these findings remains questionable. The possibility that the reciprocal nature of the effects of agonists and inverse agonists may extend to cellular signaling is discussed, and that this may account for the beneficial effects of certain p-adrenoceptor inverse agonists in the treatment of heart failure. © 2003 Elsevier Science B.V. All rights reserved. Keywords. Inverse agonism; GPCR; Paradoxical pharmacology 1. Brief history of inverse agonism at G protein-coupled receptors For approximately three-quarters of a century, ligands that interacted with G protein- coupled receptors (GPCRs) were classified either as agonists or antagonists. Receptors were thought to exist in a single quiescent state that could only induce cellular signaling upon agonist binding to the receptor to produce an activated state of the receptor. In this model, antagonists had no cellular signaling ability on their own, but did bind to the receptor and prevented agonists from being able to bind and activate the receptor.
    [Show full text]
  • Metabotropic Glutamate Receptors
    mGluR Metabotropic glutamate receptors mGluR (metabotropic glutamate receptor) is a type of glutamate receptor that are active through an indirect metabotropic process. They are members of thegroup C family of G-protein-coupled receptors, or GPCRs. Like all glutamate receptors, mGluRs bind with glutamate, an amino acid that functions as an excitatoryneurotransmitter. The mGluRs perform a variety of functions in the central and peripheral nervous systems: mGluRs are involved in learning, memory, anxiety, and the perception of pain. mGluRs are found in pre- and postsynaptic neurons in synapses of the hippocampus, cerebellum, and the cerebral cortex, as well as other parts of the brain and in peripheral tissues. Eight different types of mGluRs, labeled mGluR1 to mGluR8, are divided into groups I, II, and III. Receptor types are grouped based on receptor structure and physiological activity. www.MedChemExpress.com 1 mGluR Agonists, Antagonists, Inhibitors, Modulators & Activators (-)-Camphoric acid (1R,2S)-VU0155041 Cat. No.: HY-122808 Cat. No.: HY-14417A (-)-Camphoric acid is the less active enantiomer (1R,2S)-VU0155041, Cis regioisomer of VU0155041, is of Camphoric acid. Camphoric acid stimulates a partial mGluR4 agonist with an EC50 of 2.35 osteoblast differentiation and induces μM. glutamate receptor expression. Camphoric acid also significantly induced the activation of NF-κB and AP-1. Purity: ≥98.0% Purity: ≥98.0% Clinical Data: No Development Reported Clinical Data: No Development Reported Size: 10 mM × 1 mL, 100 mg Size: 10 mM × 1 mL, 5 mg, 10 mg, 25 mg (2R,4R)-APDC (R)-ADX-47273 Cat. No.: HY-102091 Cat. No.: HY-13058B (2R,4R)-APDC is a selective group II metabotropic (R)-ADX-47273 is a potent mGluR5 positive glutamate receptors (mGluRs) agonist.
    [Show full text]
  • The G Protein-Coupled Glutamate Receptors As Novel Molecular Targets in Schizophrenia Treatment— a Narrative Review
    Journal of Clinical Medicine Review The G Protein-Coupled Glutamate Receptors as Novel Molecular Targets in Schizophrenia Treatment— A Narrative Review Waldemar Kryszkowski 1 and Tomasz Boczek 2,* 1 General Psychiatric Ward, Babinski Memorial Hospital in Lodz, 91229 Lodz, Poland; [email protected] 2 Department of Molecular Neurochemistry, Medical University of Lodz, 92215 Lodz, Poland * Correspondence: [email protected] Abstract: Schizophrenia is a severe neuropsychiatric disease with an unknown etiology. The research into the neurobiology of this disease led to several models aimed at explaining the link between perturbations in brain function and the manifestation of psychotic symptoms. The glutamatergic hypothesis postulates that disrupted glutamate neurotransmission may mediate cognitive and psychosocial impairments by affecting the connections between the cortex and the thalamus. In this regard, the greatest attention has been given to ionotropic NMDA receptor hypofunction. However, converging data indicates metabotropic glutamate receptors as crucial for cognitive and psychomotor function. The distribution of these receptors in the brain regions related to schizophrenia and their regulatory role in glutamate release make them promising molecular targets for novel antipsychotics. This article reviews the progress in the research on the role of metabotropic glutamate receptors in schizophrenia etiopathology. Citation: Kryszkowski, W.; Boczek, T. The G Protein-Coupled Glutamate Keywords: schizophrenia; metabotropic glutamate receptors; positive allosteric modulators; negative Receptors as Novel Molecular Targets allosteric modulators; drug development; animal models of schizophrenia; clinical trials in Schizophrenia Treatment—A Narrative Review. J. Clin. Med. 2021, 10, 1475. https://doi.org/10.3390/ jcm10071475 1. Introduction Academic Editors: Andreas Reif, Schizophrenia is a common debilitating disease affecting about 0.3–1% of the human Blazej Misiak and Jerzy Samochowiec population worldwide [1].
    [Show full text]
  • Neurotransmitters-Drugs Andbrain Function.Pdf
    Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Neurotransmitters, Drugs and Brain Function Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Neurotransmitters, Drugs and Brain Function Edited by R. A. Webster Department of Pharmacology, University College London, UK JOHN WILEY & SONS, LTD Chichester Á New York Á Weinheim Á Brisbane Á Singapore Á Toronto Neurotransmitters, Drugs and Brain Function. Edited by Roy Webster Copyright & 2001 John Wiley & Sons Ltd ISBN: Hardback 0-471-97819-1 Paperback 0-471-98586-4 Electronic 0-470-84657-7 Copyright # 2001 by John Wiley & Sons Ltd. Bans Lane, Chichester, West Sussex PO19 1UD, UK National 01243 779777 International ++44) 1243 779777 e-mail +for orders and customer service enquiries): [email protected] Visit our Home Page on: http://www.wiley.co.uk or http://www.wiley.com All Rights Reserved. No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording, scanning or otherwise, except under the terms of the Copyright, Designs and Patents Act 1988 or under the terms of a licence issued by the Copyright Licensing Agency Ltd, 90 Tottenham Court Road, London W1P0LP,UK, without the permission in writing of the publisher. Other Wiley Editorial Oces John Wiley & Sons, Inc., 605 Third Avenue, New York, NY 10158-0012, USA WILEY-VCH Verlag GmbH, Pappelallee 3, D-69469 Weinheim, Germany John Wiley & Sons Australia, Ltd.
    [Show full text]
  • (12) United States Patent (10) Patent No.: US 6,469,065 B1 Garvey Et Al
    USOO6469.065B1 (12) United States Patent (10) Patent No.: US 6,469,065 B1 Garvey et al. (45) Date of Patent: Oct. 22, 2002 (54) NITROSATED AND NITROSYLATED 5,612,314 A 3/1997 Stamler et al. C-ADRENERGIC RECEPTOR ANTAGONIST, 5,635,204 A 6/1997 Gevirtz et al. .............. 424/449 COMPOSITIONS AND METHODS OF USE 5,646,181 A 7/1997 Fung et al. 5,648,393 A 7/1997 Stamler et al. 5,698,589 A 12/1997 Allen (75) Inventors: David S. Garvey, Dover; Joseph D. 5,731,339 A 3/1998 Lowrey Schroeder, Dedham, both of MA (US); 5,767,160 A 6/1998 Kaesemeyer Inigo Saenez de Tejada, Madrid (ES); 5,773,457 A 6/1998 Nahoum Ricky D. Gaston, Malden, MA (US); 5,789.442 A 8/1998 Garfield et al. Tatiana E. Shelekhin, Acton, MA 5,877,216 A 3/1999 Place et al. (US); Tiansheng Wang, Concord, MA (US) FOREIGN PATENT DOCUMENTS EP O346297 12/1989 (73) Assignee: NitroMed, Inc., Bedford, MA (US) EP O357581 3/1990 EP O432199 6/1991 (*) Notice: Subject to any disclaimer, the term of this FR 2547SO1 12/1984 patent is extended or adjusted under 35 JP 8O26962 1/1998 U.S.C. 154(b) by 0 days. WO 97/27749 * 8/1997 WO 97.27749 8/1997 WO 97.42.946 11/1997 (21) Appl. No.: 09/387,724 WO 9852569 11/1998 Filed: Sep. 1, 1999 WO 99.01132 1/1999 (22) WO 9907353 2/1999 WO 99.07695 2/1999 Related U.S.
    [Show full text]
  • Poster Abstracts
    POSTER ABSTRACTS Society of Toxicology (MASOT) www.masot.org Fall 2015 Scientific Meeting October 13th, 2015 Abstract 01 Tracking Inflammatory Macrophage Accumulation in the Lung during Ozone- induced Lung Injury in Mice M Francis, M Mandal, C. Sun, H Choi, JD Laskin, DL Laskin Rutgers University, Piscataway, NJ Ozone induced lung injury is associated with an accumulation of pro- and antiinflammatory macrophages (MP) in the lung which have been implicated in tissue injury and repair. In these studies, we used in vivo tracking techniques to investigate the origin of cell. Initially we generated bone marrow (BM) chimeric mice by adoptive transfer of BM cells from GFP+ mice into irradiated C57BL/6 mice. After 4 weeks, mice were exposed to air or ozone (0.8 ppm, 3 h). Macrophages were isolated from lungs 24- 72 h later, stained with fluorescent labeled antibodies, and analyzed by flow cytometry. Approximately 98% of BM cells were found to be GFP+ while only 5% were GFP+ in control lungs. Ozone exposure resulted in a marked increase in infiltrating mature GFP+CD11b+F4/80+ MP into the lung. Two populations, Ly6CHi proinflammatory and Ly6CLo antiinflammatory were identified. Proinflammatory GFP+Ly6CHi MP increased rapidly after ozone and remained elevated, increases in antiinflammatory GFP+Ly6CLo were transient. To assess potential mechanisms mediating the accumulation of these MP subpopulations in the lung, we used mice lacking Ccr2, a chemokine receptor involved in proinflammatory MP trafficking. Loss of Ccr2 resulted in decreased numbers of infiltrating CD11b+ MP in the lung. This was due to a selective reduction in proinflammatory Ly6CHi MP.
    [Show full text]