DOCSLIB.ORG

2 11/044535 A2

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
2 11/044535 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date _ . 14 April 2011 (14.04.2011) 2 11/044535 A2 (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 471/04 (2006.01) A61P 25/18 (2006.01) kind of national protection available): AE, AG, AL, AM, C07D 413/14 (2006.01) A61P 25/28 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, C07D 409/14 (2006.01) A61P 25/24 (2006.01) CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, A61K 31/519 (2006.01) DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, (21) International Application Number: KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, PCT/US20 10/052 106 ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, (22) International Filing Date: NO, NZ, OM, PE, PG, PH, PL, PT, RO, RS, RU, SC, SD, 8 October 2010 (08.10.2010) SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (25) Filing Language: English (84) Designated States (unless otherwise indicated, for every (26) Publication Language: English kind of regional protection available): ARIPO (BW, GH, (30) Priority Data: GM, KE, LR, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, 61/250,262 >October 2009 (09.10.2009) US ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, 61/353,054 9 June 2010 (09.06.2010) US TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, ΓΓ, LT, LU, (71) Applicant (for all designated States except US): LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, AFRAXIS, INC. [US/US]; 5626 Oberlin Drive, San SM, TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, Diego, California 92121 (US). GW, ML, MR, NE, SN, TD, TG). (72) Inventors; and Declarations under Rule 4.17 : (75) Inventors/Applicants (for US only): VOLLRATH, — as to applicant's entitlement to apply for and be granted Benedikt [DE/US]; 4704 Niagara Avenue, San Diego, a patent (Rule 4.1 7(H)) California 92107 (US). CAMPBELL, David [US/US]; 1331 8 Seagrove Street, San Diego, California 92130 — as to the applicant's entitlement to claim the priority of (US). DURON, Sergio G. [US/US]; 1605 Neale Street, the earlier application (Rule 4.17(Hi)) San Diego, California 92103 (US). WADE, Warren [US/ Published: US]; 10940 Shy Bird Lane, San Diego, California 92128 (US). — without international search report and to be republished upon receipt of that report (Rule 48.2(g)) (74) Agents: WILSON SONSINI GOODRICH & ROSATI et al; 650 Page Mill Road, Palo Alto, California 94304 (US). < o (54) Title: 8-ETHYL-6-(ARYL)PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONES FOR THE TREATMENT OF CNS DISORDERS (57) Abstract: Provided herein are PAK inhibitors and methods of utilizing PAK inhibitors for the treatment of CNS disorders such as neuropsychiatric disorders. 8-ETHYL-6-(ARYL)PYRIDO[2,3-D]PYRIMIDIN-7(8H)-ONES FOR THE TREATMENT OF CNS DISORDERS CROSS-REFERENCE [0001] This application claims the benefit of U.S. Provisional Application No. 61/250,262, filed October 9, 2009, and U.S. Provisional Application No. 61/353,054, filed June 9, 2010, which are both incorporated herein by reference in their entirety. BACKGROUND OF THE INVENTION [0002] Central Nervous System (CNS) disorders are characterized by a variety of debilitating affective and cognitive impairments. For example, a clinical sign of individuals with Alzheimer's disease is progressive cognition deterioration. Worldwide, approximately 24 million people have dementia, 60% of these cases are due to Alzheimer's. [0003] Other CNS disorders include, e.g., mood disorders, age-related cognitive decline, and neurological disorders (e.g., epilepsy, schizophrenia, Fragile X mental retardation syndrome and Huntington's disease). The effects of CNS disorders are devastating to the quality of life of those afflicted as well as that of their families. Moreover, CNS disorders impose an enormous health care burden on society. A number of CNS disorders, as well as other conditions that affect cognitive function, have been associated with alterations in the morphology and/or density of dendritic spines, membranous protrusions from dendritic shafts of neurons that serve as highly specialized structures for the formation, maintenance, and function of synapses. SUMMARY OF THE INVENTION [0004] Described herein are compounds, compositions and methods for treating an individual suffering from a CNS disorder, such as by way of example only schizophrenia, Fragile X Syndrome (FXS), clinical depression, age-related cognitive decline, Mild Cognitive Impairment, Huntington's disease, Parkinson's disease, neurofibromatosis, Alzheimer's disease, epilepsy, autism spectrum disorders, mental retardation, Down's syndrome or the like, by administering to an individual a pharmaceutical composition comprising a therapeutically effective amount of an inhibitor of a p21 -activated kinase (PAK), e.g., an inhibitor of PAK1, PAK2, PAK3 or PAK4, as described herein. PAK activation is shown to play a key role in spine morphogenesis. In some instances, attenuation of PAK activity reduces, prevents or reverses defects in spine morphogenesis. In some embodiments, inhibitors of one or more of Group I PAKs (PAK1, PAK2 and/or PAK3) and/or Group II PAKs (PAK4, PAK5 and/or PAK6) are administered to rescue defects in spine morphogenesis in individuals suffering from a condition in which dendritic spine morphology, density, and/or function are aberrant, including but not limited to abnormal spine density, spine size, spine shape, spine plasticity, spine motility or spine plasticity leading to improvements in synaptic function, cognition and/or behavior. [0005] In one aspect is a compound having the structure of Formula I or pharmaceutically acceptable salt or N-oxide thereof: Formula I; wherein: wherein ring T is an aryl, or a heteroaryl ring; R3 is a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heteroaryl attached to ring T via a carbon atom of R , or a substituted or unsubstituted heterocycloalkyl attached to ring T via a carbon atom of R ; Q is a substituted or unsubstituted alkyl, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted cycloalkylalkyl, a substituted or unsubstituted heterocycloalkylalkyl, a substituted or unsubstituted aryl, a substituted or unsubstituted arylalkyl, a substituted or unsubstituted heteroaryl, or a substituted or unsubstituted heteroarylalkyl; 4 each R is independently halogen, -CN, -N0 2, -OH, -OCF3, -OCH2F, -OCF2H, -CF3, 8 10 9 10 8 9 10 -SR , -NR S(=O)2R , -S(=O)2N(R )2, -C(=0)R , -OC(=0)R , -C0 2R , 10 10 10 10 10 10 -N(R )2, -C(=O)N(R )2, -NR C(=O)R , -N R C(=O)OR , 10 10 -NR C(=O)N(R )2, a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; R8 is H or R9; R9 is a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; each R10 is independently H, a substituted or unsubstituted alkyl, a substituted or unsubstituted cycloalkyl, a substituted or unsubstituted heterocycloalkyl, a substituted or unsubstituted aryl, or a substituted or unsubstituted heteroaryl; or two R10, together with the atoms to which they are attached form a heterocycle; ring B is aryl or heteroaryl; 5 8 9 9 each R is independently halogen, -CN, -N0 2, -OH, -SR , -S(=0)R , -S(=0) 2R , 10 9 10 8 9 10 10 NR S(=O)2R , -S(=O)2N(R )2, -C(=0)R , -OC(=0)R , -C0 2R , -N(R )2, - 10 10 10 10 10 10 10 10 C(=O)N(R )2, -NR C(=O)R , -NR C(=O)OR , -NR C(=O)N(R )2, -OR , a substituted or unsubstituted alkyl, a substituted or unsubstituted alkoxy, a substituted or unsubstituted heteroalkyl, a substituted or unsubstituted cycloalkyl, or a substituted or unsubstituted heterocycloalkyl; r is 0 to 8; and s is 0 to 4. [0006] In one embodiment is a compound of Formula I wherein ring T is an aryl ring. In another embodiment is a compound of Formula I wherein ring T is a heteroaryl ring. In yet another embodiment is a compound of Formula I, wherein ring T is selected from pyrrole, furan, thiophene, pyrazole, imidazole, isoxazole, oxazole, isothiazole, thiazole, 1,2,3-triazole, 1,3,4-triazole, l-oxa-2,3-diazole, l-oxa-2,4-diazole, l-oxa-2,5-diazole, 1-oxa- 3,4-diazole, l-thia-2,3-diazole, 1-thia-2,4-diazole, l-thia-2,5-diazole, l-thia-3,4-diazole, tetrazole, pyridine, pyridazine, pyrimidine, and pyrazine. In yet a further embodiment is a compound of Formula I, wherein R is a C-linked heterocycloalkyl. In another embodiment is a compound of Formula I, wherein R is a substituted or unsubstituted C-linked heteroaryl. In another embodiment, R3 is a substituted or unsubstituted cycloalkyl. In a further embodiment, cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. [0007] In yet another embodiment is a compound having the structure of Formula II: Formula II. [0008] In a further embodiment is a compound having the structure of Formula III: Formula III; wherein si is 0 to 3.
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]
  • Infiltrating Myeloid Cells Drive Osteosarcoma Progression Via GRM4 Regulation of IL23
    Published OnlineFirst September 16, 2019; DOI: 10.1158/2159-8290.CD-19-0154 RESEARCH BRIEF Infi ltrating Myeloid Cells Drive Osteosarcoma Progression via GRM4 Regulation of IL23 Maya Kansara 1 , 2 , Kristian Thomson 1 , Puiyi Pang 1 , Aurelie Dutour 3 , Lisa Mirabello 4 , Francine Acher5 , Jean-Philippe Pin 6 , Elizabeth G. Demicco 7 , Juming Yan 8 , Michele W.L. Teng 8 , Mark J. Smyth 9 , and David M. Thomas 1 , 2 ABSTRACT The glutamate metabotropic receptor 4 (GRM4 ) locus is linked to susceptibility to human osteosarcoma, through unknown mechanisms. We show that Grm4 − / − gene– targeted mice demonstrate accelerated radiation-induced tumor development to an extent comparable with Rb1 +/ − mice. GRM4 is expressed in myeloid cells, selectively regulating expression of IL23 and the related cytokine IL12. Osteosarcoma-conditioned media induce myeloid cell Il23 expression in a GRM4-dependent fashion, while suppressing the related cytokine Il12 . Both human and mouse osteosarcomas express an increased IL23:IL12 ratio, whereas higher IL23 expression is associated with worse survival in humans. Con- sistent with an oncogenic role, Il23−/− mice are strikingly resistant to osteosarcoma development. Agonists of GRM4 or a neutralizing antibody to IL23 suppressed osteosarcoma growth in mice. These fi ndings identify a novel, druggable myeloid suppressor pathway linking GRM4 to the proinfl ammatory IL23/IL12 axis. SIGNIFICANCE: Few novel systemic therapies targeting osteosarcoma have emerged in the last four decades. Using insights gained from a genome-wide association study and mouse modeling, we show that GRM4 plays a role in driving osteosarcoma via a non–cell-autonomous mechanism regulating IL23, opening new avenues for therapeutic intervention.
    [Show full text]
  • Herbal Contraindications & Drug Interactions
    Herbal Contraindications & Drug Interactions plus Herbal Adjuncts with Medicines FOURTH EDITION, 2010 © by Francis Brinker, N.D. References 1. Sherman JA (comp.). The Complete Botanical Prescriber, 2nd ed. National College of Naturopathic Medicine, Portland, Ore., 1979 2. Brinker F. The Toxicology of Botanical Medicines, 3rd ed. Eclectic Medical Pub., Sandy, Ore., 2000 3. Brinker F. “Botanical Medicine Research Summaries,” from Eclectic Dispensatory of Botanical Therapeutics, vol. II. Eclectic Medical Pub., Sandy, Ore., 1995 4. Wichtl M (ed.). Herbal Drugs and Phytopharmaceuticals. CRC Press, Boca Raton, 1994 5. Felter HW, Lloyd JU. King’s American Dispensatory [1898]. Eclectic Medical Pub., Sandy, Ore., 1993 6. De Smet PAGM et al. (eds.). Adverse Effects of Herb Drugs 2. Springer-Verlag, Berlin, 1993 7. Lust J. The Herb Book. Bantam Books, New York, 1974 8. Boyd JR (ed.-in-chief). Facts and Comparisons. J.B. Lippincott Co., St. Louis, Miss., 1985 9. Ruddiman EA. Incompatibilities in Prescriptions. John Wiley & Sons, Inc., New York, 1925 10. Lewis WH, Elvin-Lewis MPF. Medical Botany. John Wiley & Sons, New York, 1977 11. Gibelli C. The hemostatic action of Equisetum. Arch. intern. pharmacodynamie, 41:419-429, 1931 (Chem. Abs. 26:6019) 12. Gutierrez RMP, Laguna GY, Walkowski, A. diuretic activity of Mexican Equisetum. J. Ethnopharm., 14:269- 272, 1985 13. Lepor H. Nonoperative management of benign prostatic hyperplasia. J. Urol., 141:1283-1289, 1989 14. Albert-Puleo M. Fennel and anise as estrogenic agents. J. Ethnopharm., 2:337-344, 1980 15. Albert-Puleo M. Mythobotany, pharmacology, and chemistry of thujone-containing plants and derivatives. Econ. Bot., 32:65-74, 1978 16.
    [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]
  • Front Matter
    zpt0040800SPC1.qxd 3/11/08 10:55 AM Page 1 Volume 325 ■ Number 1 ■ April 2008 ■ ISSN 0022-3565 The Journal of PHARMACOLOGY And Experimental Therapeutics A Adaptations (Network Architecture) Can Create Unpredicted Therapeutic Actions Drug Predicted Effect Unexpected Effect B Complexity Creates Unpredicted Targets Predicted Effect Drug Target Unpredicted Target A Publication of the American Society for Pharmacology and Experimental Therapeutics Edited for the Society by Rick G. Schnellmann The Journal of PHARMACOLOGY And Experimental Therapeutics A Publication of the American Society for Pharmacology and Experimental Therapeutics April 2008 Vol. 325, No. 1 Contents PERSPECTIVES IN PHARMACOLOGY Exploiting Complexity and the Robustness of Network Marc K. Hellerstein 1 Architecture for Drug Discovery BEHAVIORAL PHARMACOLOGY Early Postnatal Stress Alters Place Conditioning to Both ␮- and Clifford C. Michaels and Stephen G. Holtzman 313 ␬-Opioid Agonists CARDIOVASCULAR □ ␤ S Design of Mutant 2 Subunits as Decoy Molecules to Reduce the Sabine Te´le´maque, Swapnil Sonkusare, 37 ,Expression of Functional Ca2؉ Channels in Cardiac Cells Terrie Grain, Sung W. Rhee, Joseph R. Stimers Nancy J. Rusch, and James D. Marsh Sphingosine 1-Phosphate Inhibits Nitric Oxide Production Takuji Machida, Yukihiro Hamaya, 200 Induced by Interleukin-1␤ in Rat Vascular Smooth Muscle Cells Sachiko Izumi, Yumika Hamaya, Kenji Iizuka, Yasuyuki Igarashi, Masaru Minami, Roberto Levi, and Masahiko Hirafuji Andrographolide Up-Regulates Cellular-Reduced Glutathione Anthony Y. H. Woo, Mary M. Y. Waye, 226 Level and Protects Cardiomyocytes against Stephen K. W. Tsui, Sandy T. W. Yeung, and Hypoxia/Reoxygenation Injury Christopher H. K. Cheng Orally Available Levosimendan Dose-Related Positive Inotropic Satoshi Masutani, Heng-Jie Cheng, 236 and Lusitropic Effect in Conscious Chronically Instrumented Minja Hyttila¨-Hopponen, Jouko Levijoki, Normal and Heart Failure Dogs Aira Heikkila¨, Arja Vuorela, William C.
    [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]
  • Treatment Protocol Copyright © 2018 Kostoff Et Al
    Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al PREVENTION AND REVERSAL OF ALZHEIMER'S DISEASE: TREATMENT PROTOCOL by Ronald N. Kostoffa, Alan L. Porterb, Henry. A. Buchtelc (a) Research Affiliate, School of Public Policy, Georgia Institute of Technology, USA (b) Professor Emeritus, School of Public Policy, Georgia Institute of Technology, USA (c) Associate Professor, Department of Psychiatry, University of Michigan, USA KEYWORDS Alzheimer's Disease; Dementia; Text Mining; Literature-Based Discovery; Information Technology; Treatments Prevention and reversal of Alzheimer's disease: treatment protocol Copyright © 2018 Kostoff et al CITATION TO MONOGRAPH Kostoff RN, Porter AL, Buchtel HA. Prevention and reversal of Alzheimer's disease: treatment protocol. Georgia Institute of Technology. 2018. PDF. https://smartech.gatech.edu/handle/1853/59311 COPYRIGHT AND CREATIVE COMMONS LICENSE COPYRIGHT Copyright © 2018 by Ronald N. Kostoff, Alan L. Porter, Henry A. Buchtel Printed in the United States of America; First Printing, 2018 CREATIVE COMMONS LICENSE This work can be copied and redistributed in any medium or format provided that credit is given to the original author. For more details on the CC BY license, see: http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License<http://creativecommons.org/licenses/by/4.0/>. DISCLAIMERS The views in this monograph are solely those of the authors, and do not represent the views of the Georgia Institute of Technology or the University of Michigan. This monograph is not intended as a substitute for the medical advice of physicians. The reader should regularly consult a physician in matters relating to his/her health and particularly with respect to any symptoms that may require diagnosis or medical attention.
    [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]
  • Are Anti-Amyloid Therapies Still Worth Being Developed As Treatments For
    Viewpoints Are Anti-amyloid Therapies Still Worth Being Developed as Treatments for Alzheimer’s Disease? Despite limited pharmaceutical success thus far, amyloid peptides may yet prove useful in the treatment of Alzheimer’s and delay disease progression. By Laurent Lecanu, DPharm, PhD rug discovery in the domain of Alzheimer’s obstacle lies in the multiplicity of the deleterious disease is essentially benchmarked by clinical pathways that are activated during the progression trial failures (dimebon, tramiprosate, taren- of the disease, probably at distinct time points. Dflurbil, semagacestat, the vaccine AN1752).1-6 These multiple pathways explain the limited efficacy Difficulty in finding an AD treatment arises from of the classical single-target drugs. Future treatments lack of knowledge of the origin of this disease. for AD will necessarily include drugs aimed at dif- Although the etiology of the familial form of AD is ferent targets. Alternatively, in accord with the cur- known, that of the sporadic form, which represents rent trend, they will evolve toward the development 95 percent of the cases, remains unidentified.7 of compounds8 that target several mechanisms lead- Consequently, most animal models currently used in ing to different pathological endpoints. the proof-of-concept stage of preclinical studies in For a long time, the scientific community has pri- AD R&D were developed based on knowledge marily focused on improving cholinergic network acquired from studying the familial form of AD. dysfunction for the treatment of AD. This led to the This represents a second obstacle in finding AD development of the therapeutic class of acetyl- treatments, as these models have limited usefulness cholinesterase inhibitors (AchEI), with tacrine as the for studying the sporadic form of the disease and as class leader.
    [Show full text]
  • Dynamic L-Glutamate Signaling in the Prefrontal Cortex and the Effects of Methylphenidate Treatment
    University of Kentucky UKnowledge Theses and Dissertations--Neuroscience Neuroscience 2012 DYNAMIC L-GLUTAMATE SIGNALING IN THE PREFRONTAL CORTEX AND THE EFFECTS OF METHYLPHENIDATE TREATMENT Catherine Elizabeth Mattinson University of Kentucky, [email protected] Right click to open a feedback form in a new tab to let us know how this document benefits ou.y Recommended Citation Mattinson, Catherine Elizabeth, "DYNAMIC L-GLUTAMATE SIGNALING IN THE PREFRONTAL CORTEX AND THE EFFECTS OF METHYLPHENIDATE TREATMENT" (2012). Theses and Dissertations--Neuroscience. 4. https://uknowledge.uky.edu/neurobio_etds/4 This Doctoral Dissertation is brought to you for free and open access by the Neuroscience at UKnowledge. It has been accepted for inclusion in Theses and Dissertations--Neuroscience by an authorized administrator of UKnowledge. For more information, please contact [email protected]. STUDENT AGREEMENT: I represent that my thesis or dissertation and abstract are my original work. Proper attribution has been given to all outside sources. I understand that I am solely responsible for obtaining any needed copyright permissions. I have obtained and attached hereto needed written permission statements(s) from the owner(s) of each third-party copyrighted matter to be included in my work, allowing electronic distribution (if such use is not permitted by the fair use doctrine). I hereby grant to The University of Kentucky and its agents the non-exclusive license to archive and make accessible my work in whole or in part in all forms of media, now or hereafter known. I agree that the document mentioned above may be made available immediately for worldwide access unless a preapproved embargo applies.
    [Show full text]
  • Tanibirumab (CUI C3490677) Add to Cart
    5/17/2018 NCI Metathesaurus Contains Exact Match Begins With Name Code Property Relationship Source ALL Advanced Search NCIm Version: 201706 Version 2.8 (using LexEVS 6.5) Home | NCIt Hierarchy | Sources | Help Suggest changes to this concept Tanibirumab (CUI C3490677) Add to Cart Table of Contents Terms & Properties Synonym Details Relationships By Source Terms & Properties Concept Unique Identifier (CUI): C3490677 NCI Thesaurus Code: C102877 (see NCI Thesaurus info) Semantic Type: Immunologic Factor Semantic Type: Amino Acid, Peptide, or Protein Semantic Type: Pharmacologic Substance NCIt Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor tyrosine kinase expressed by endothelial cells, while VEGF is overexpressed in many tumors and is correlated to tumor progression. PDQ Definition: A fully human monoclonal antibody targeting the vascular endothelial growth factor receptor 2 (VEGFR2), with potential antiangiogenic activity. Upon administration, tanibirumab specifically binds to VEGFR2, thereby preventing the binding of its ligand VEGF. This may result in the inhibition of tumor angiogenesis and a decrease in tumor nutrient supply. VEGFR2 is a pro-angiogenic growth factor receptor
    [Show full text]
  • Convergent Pharmacological Mechanisms in Impulsivity And
    British Journal of DOI:10.1111/bph.12787 www.brjpharmacol.org BJP Pharmacology Themed Section: Animal Models in Psychiatry Research Correspondence Jeffrey W Dalley, Department of Psychology, University of REVIEW Cambridge, Downing St, Cambridge CB2 3EB, UK. E-mail: [email protected] Convergent ---------------------------------------------------------------- Received 20 February 2014 pharmacological Revised 2 May 2014 Accepted mechanisms in impulsivity 12 May 2014 and addiction: insights from rodent models B Jupp1,2 and J W Dalley1,3 1Behavioural and Clinical Neuroscience Institute and Department of Psychology, University of Cambridge, Cambridge, UK, 2Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Australia, and 3Department of Psychiatry, University of Cambridge, Cambridge, UK Research over the last two decades has widely demonstrated that impulsivity, in its various forms, is antecedent to the development of drug addiction and an important behavioural trait underlying the inability of addicts to refrain from continued drug use. Impulsivity describes a variety of rapidly and prematurely expressed behaviours that span several domains from impaired response inhibition to an intolerance of delayed rewards, and is a core symptom of attention deficit hyperactivity disorder (ADHD) and other brain disorders. Various theories have been advanced to explain how impulsivity interacts with addiction both causally and as a consequence of chronic drug abuse; these acknowledge the strong overlaps in neural circuitry and mechanisms between impulsivity and addiction and the seemingly paradoxical treatment of ADHD with stimulant drugs with high abuse potential. Recent years have witnessed unprecedented progress in the elucidation of pharmacological mechanisms underpinning impulsivity. Collectively, this work has significantly improved the prospect for new therapies in ADHD as well as our understanding of the neural mechanisms underlying the shift from recreational drug use to addiction.
    [Show full text]