DOCSLIB.ORG

(12) United States Patent (10) Patent N0.: US 7,964,607 B2 Verhoest Et A1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
(12) United States Patent (10) Patent N0.: US 7,964,607 B2 Verhoest Et A1 US007964607B2 (12) United States Patent (10) Patent N0.: US 7,964,607 B2 Verhoest et a1. (45) Date of Patent: Jun. 21, 2011 (54) PYRAZOLO[3,4-D]PYRIMIDINE FOREIGN PATENT DOCUMENTS COMPOUNDS EP 1460077 9/2004 WO 02085904 10/2002 (75) Inventors: Patrick Robert Verhoest, Old Lyme, CT WO 2004037176 5/2004 (US); Caroline ProulX-Lafrance, Ledyard, CT (US) OTHER PUBLICATIONS Wunder et a1, M01. PharmacoL, v01. 28, N0. 6, (2005), pp. 1776 (73) Assignee: P?zer Inc., New York, NY (U S) 1781. van der Staay et a1, Neuropharmacology, v01. 55 (2008), pp. 908 ( * ) Notice: Subject to any disclaimer, the term of this 918. patent is extended or adjusted under 35 USC 154(b) by 562 days. Primary Examiner * Susanna Moore (74) Attorney, Agent, or Firm * Jennifer A. Kispert; (21) Appl.No.: 12/118,062 Michael Herman (22) Filed: May 9, 2008 (57) ABSTRACT (65) Prior Publication Data The invention provides PDE9-inhibiting compounds of For US 2009/0030003 A1 Jan. 29, 2009 mula (I), Related US. Application Data (60) Provisional application No. 60/917,333, ?led on May 11, 2007. (51) Int. Cl. C07D 48 7/04 (2006.01) A61K 31/519 (2006.01) A61P 25/28 (2006.01) (52) US. Cl. ................................... .. 514/262.1; 544/262 (58) Field of Classi?cation Search ................ .. 544/262; 5 1 4/2 62 .1 See application ?le for complete search history. and pharmaceutically acceptable salts thereof, Wherein R, R1, (56) References Cited R2 and R3 are as de?ned herein. Pharmaceutical compositions containing the compounds of Formula I, and uses thereof in U.S. PATENT DOCUMENTS treating neurodegenerative and cognitive disorders, such as 2003/0139427 A1 7/2003 Castelhano et a1. ..... .. 514/2611 AlZheimer’s disease and schizophrenia, are also provided. 2004/0176361 A1 9/2004 Fujio et a1. ............... .. 514/2242 2004/0259870 A1 12/2004 Feng et a1. ............... .. 514/2292 13 Claims, No Drawings US 7,964,607 B2 1 2 PYRAZOLO[3,4-D]PYRIMIDINE 47: 1081-1092 (2004). Inhibition of PDE9 has been shoWn to COMPOUNDS increase LTP. Hendrix, BMC PharmacoL, 5(Supp 1):55 (2005). RELATED APPLICATION Accordingly, there is a need for PDE9 inhibitors that are effective in treating conditions that may be regulated or nor This application claims the bene?t under 35 U.S.C. §119 maliZed by inhibition of PDE9. (e) of Us. provisional application Ser. No. 60/917,333, ?led May 11, 2007. SUMMARY OF THE INVENTION FIELD OF THE INVENTION The present invention is directed to compounds of Formula (I), This invention relates to a series of novel compounds that are selective inhibitors of phosphodiesterase type 9 (“PDE9”). More particularly, the invention relates to pyra (I) Zolo[3,4-d]pyrimidinone compounds for use in the treatment and prevention of neurodegenerative diseases and other dis eases and disorders in?uenced by modulation of PDE9. BACKGROUND OF THE INVENTION 20 Cyclic nucleotides cyclic guanosine monophosphate (cGMP) and cyclic adenosine monophosphate (cAMP) are important second messengers and thus are central to the con trol and regulation of a multitude of cellular events, both physiological and pathophysiological, in a Wide variety of 25 organs. and pharmaceutically acceptable salts thereof, Wherein R, R1, Cyclic GMP is formed from GTP by the catalytic reaction R2, and R3 are as de?ned herein. of guanylyl cyclase (GC), Which is activated by nitric oxide The present invention is also directed to compositions con (NO). Cyclic GMP in turn activates cGMP-dependent protein taining a compound of Formula (I), or a pharmaceutically kinases (cGK), Which mediate localiZed and global signaling. 30 acceptable salt thereof, and a pharmaceutically acceptable A variety of physiological processes in the cardiovascular, vehicle, carrier or diluent, and optionally further comprising nervous and immune systems are controlled by the a second pharmaceutical agent. NO/cGMP pathWay, including ion channel conductance, gly The present invention is further directed to a method of cogenolysis, cellular apoptosis, and smooth muscle relax inhibiting PDE9 in a mammal in need of such inhibition, ation. Inblood vessels, relaxation of vascular smooth muscles 35 comprising the step of administering to the mammal a PDE9 leads to vasodilation and increased blood How. inhibiting amount of a) a compound of Formula I, or a phar The phosphodiesterase (PDE) enZyme family hydrolyses maceutically acceptable salt thereof; or b) a pharmaceutical cGMP and cAMP. The PDE9 enZyme has been identi?ed as a composition comprising a compound of Formula I, or a phar novel member of the PDE enZyme family that selectively maceutically acceptable salt thereof, and a pharmaceutically hydrolyses cGMP over cAMP. See Fisher et al., J. Biol. 40 acceptable vehicle, carrier or diluent. Chem, 273(25), 15559-15564 (1998). PDE9 has been found to be present in a variety of human tissues, namely the testes, The present invention is further directed to a method of brain, small intestine, skeletal muscle, heart, lung, thymus treating a neurodegenerative disease in a mammal in need of and spleen, as Well as in smooth muscle cells Within the such treatment, comprising the step of administering to the human vasculature of a variety of tissues. 45 mammal a therapeutically effective amount of a compound of Recent studies have directly implicated dysfunction of Formula I, or a pharmaceutically acceptable salt thereof. NO/cGMP/cGK signaling in AlZheimer’s disease. For The present invention is further directed to a method of example, disruption of Long Term Potentiation (LTP), a promoting neurorestoration in a mammal in need of such physiological correlate of learning and memory, by amy neurorestoration, comprising the step of administering to the loid-[3 peptide Was shoWn to result from a malfunction of 50 mammal a therapeutically effective amount of a compound of NO/cGMP signaling. PuZZo et al., J. Neurosci., 25(29):6887 Formula I, or a pharmaceutically acceptable salt thereof. 6897 (2005). Moreover, in rats shoWing de?cits in memory The present invention is still further directed to a method of tasks due to depletion in forebrain acetylcholinesterase improving cognitive de?cits and treating cognitive impair (Which is associated With AlZheimer’s disease), administra ment in a mammal in need of such improvement or treatment, tion of a nitric oxide mimetic increased GC activity and 55 comprising the step of administering to the mammal a thera reversed the cognitive de?cits in memory tasks. Bennett et al., peutically effective amount of a compound of Formula I, or a Neuropsychopharmacology, 321505-513 (2007). It is there pharmaceutically acceptable salt thereof. fore believed that therapeutic agents capable of enhancing the With the foregoing and other advantages and features of the GC/NO/cGMP/cGK signaling cascade may be useful as a invention that Will become hereinafter apparent, the nature of neW approach to the treatment of AlZheimer’s disease and 60 the invention may be more clearly understood by reference to other neurodegenerative disorders. the folloWing detailed description of the invention and the By reducing or preventing the hydrolysis of cGMP by appended claims. PDE9, PDE9 inhibitors elevate the intracellular level of cGMP, thus enhancing or prolonging its effects. It has been DETAILED DESCRIPTION OF THE INVENTION found that an increase in cGMP concentration in rats leads to 65 improvement in learning and memory in social and object The present invention comprises novel selective PDE9 recognition tests. See, e.g., Boess et al., Neuropharmacology, inhibitors of Formula (I), US 7,964,607 B2 1 3 1 4 1-cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(4-methyl-3,4 1-cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(2-propylpyri dihydro-2H-1,4-benZoxaZin-7-yl)methyl]pyrrolidin-3-yl} midin-5-yl)methyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyra 1,5 -dihydro -4H-pyraZolo [3 ,4-d]pyrimidin-4 -one; Zolo[3,4-d]pyrimidin-4-one; 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(3 -phenylpro 1 -cyclopentyl-6-{(3,4-trans)-1-[(1-ethyl-1H-pyraZol-5 pyl)pyrrolidin-3-yl]-1,5 -dihydro-4H-pyraZolo [3 ,4-d]pyrimi 5 yl)methyl] -4 -methylpyrrolidin-3 -yl} - 1 , 5 -dihydro -4H-pyra din-4-one; Zolo[3,4-d]pyrimidin-4-one; 1-cyclopentyl-6-{(3,4-trans)-4-methyl-1-[2-(tri?uorom 1-cyclopentyl-6-{(3,4-trans)-4-methyl-1-[2-(tri?uo ethyl)benZyl]pyrrolidin-3 -yl} - 1 ,5 -dihydro-4H-pyraZolo [3, romethoxy)benZyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyra 4-d]pyrimidin-4 -one; Zolo[3,4-d]pyrimidin-4-one; 1-cyclopentyl-6-[(3,4-trans)-4-methyl-1-(4,4,4-tri?uo 1-cyclopentyl-6-{(3,4-trans)-4-methyl-1-[4-(tri?uorom robutyl)pyrrolidin-3-yl]-1,5 -dihydro-4H -pyraZolo [3 ,4-d]py ethyl)benZyl]pyrrolidin-3-yl}-1,5-dihydro-4H-pyraZolo[3, rimidin-4-one; 4-d]pyrimidin-4-one; 1-cyclopentyl-6-[(3,4-trans)-1-(3-methoxybenZyl)-4-me 1-cyclopentyl-6-{(3,4-trans)-4-methyl-1-[(1-methyl-1H thylpyrrolidin-3 -yl]-1,5 -dihydro -4H-pyraZolo [3 ,4-d]pyrimi imidaZo[4,5-c]pyridin-2-yl)methyl]pyrrolidin-3-yl}-1,5-di din-4-one; hydro-4H-pyraZolo[3,4-d]pyrimidin-4-one; 1-cyclopentyl-6-[(3,4-trans)-1-(cyclopentylmethyl)-4 1-cyclopentyl-6-[(3,4-trans)-1-(3,5-di?uorobenZyl)-4 methylpyrrolidin-3-yl]-1,5 -dihydro-4H-pyraZolo[3 ,4-d]py methylpyrrolidin-3 -yl]-1,5-dihydro-4H-pyraZolo[3,4-d]py rimidin-4-one; rimidin-4-one; or 1-cyclopentyl-6-[(3,4-trans)-1-(2,4-dimethoxybenZyl)-4 20 1-cyclopentyl-6-[(3,4-trans)-1-(5,6-dihydro-4H-pyrrolo methylpyrrolidin-3-yl]-1,5 -dihydro-4H-pyraZolo[3 ,4-d]py [1 ,2-b]pyraZol-3 -ylmethyl)-4-methylpyrrolidin-3-yl] -1 ,5 rimidin-4-one; dihydro-4H-pyraZolo[3,4-d]pyrimidin-4-one; 1-cyclopentyl-6-{(3,4-trans)-4-methyl-1-[4-(morpholin or a pharmaceutically acceptable salt thereof.
Load more

Recommended publications
  • Opioid-Induced Hyperalgesia in Humans Molecular Mechanisms and Clinical Considerations
    SPECIAL TOPIC SERIES Opioid-induced Hyperalgesia in Humans Molecular Mechanisms and Clinical Considerations Larry F. Chu, MD, MS (BCHM), MS (Epidemiology),* Martin S. Angst, MD,* and David Clark, MD, PhD*w treatment of acute and cancer-related pain. However, Abstract: Opioid-induced hyperalgesia (OIH) is most broadly recent evidence suggests that opioid medications may also defined as a state of nociceptive sensitization caused by exposure be useful for the treatment of chronic noncancer pain, at to opioids. The state is characterized by a paradoxical response least in the short term.3–14 whereby a patient receiving opioids for the treatment of pain Perhaps because of this new evidence, opioid may actually become more sensitive to certain painful stimuli. medications have been increasingly prescribed by primary The type of pain experienced may or may not be different from care physicians and other patient care providers for the original underlying painful condition. Although the precise chronic painful conditions.15,16 Indeed, opioids are molecular mechanism is not yet understood, it is generally among the most common medications prescribed by thought to result from neuroplastic changes in the peripheral physicians in the United States17 and accounted for 235 and central nervous systems that lead to sensitization of million prescriptions in the year 2004.18 pronociceptive pathways. OIH seems to be a distinct, definable, One of the principal factors that differentiate the use and characteristic phenomenon that may explain loss of opioid of opioids for the treatment of pain concerns the duration efficacy in some cases. Clinicians should suspect expression of of intended use.
    [Show full text]
  • WO 2017/145013 Al 31 August 2017 (31.08.2017) P O P C T
    (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 WO 2017/145013 Al 31 August 2017 (31.08.2017) P O P C T (51) International Patent Classification: (81) Designated States (unless otherwise indicated, for every C07D 498/04 (2006.01) A61K 31/5365 (2006.01) kind of national protection available): AE, AG, AL, AM, C07D 519/00 (2006.01) A61P 25/00 (2006.01) AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DJ, DK, DM, (21) Number: International Application DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, PCT/IB20 17/050844 HN, HR, HU, ID, IL, IN, IR, IS, JP, KE, KG, KH, KN, (22) International Filing Date: KP, KR, KW, KZ, LA, LC, LK, LR, LS, LU, LY, MA, 15 February 2017 (15.02.2017) MD, ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, (25) Filing Language: English RU, RW, SA, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, (26) Publication Language: English TH, TJ, TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW. (30) Priority Data: 62/298,657 23 February 2016 (23.02.2016) US (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (71) Applicant: PFIZER INC. [US/US]; 235 East 42nd Street, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, ST, SZ, New York, New York 10017 (US).
    [Show full text]
  • Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking
    Neuropsychopharmacology (2013) 38, 2657–2665 & 2013 American College of Neuropsychopharmacology. All rights reserved 0893-133X/13 www.neuropsychopharmacology.org Role of a Hippocampal Src-Family Kinase-Mediated Glutamatergic Mechanism in Drug Context-Induced Cocaine Seeking 1 1 1 1 ,1 Xiaohu Xie , Amy A Arguello , Audrey M Wells , Andrew M Reittinger and Rita A Fuchs* 1 Department of Psychology, University of North Carolina, Chapel Hill, NC, USA Glutamatergic neurotransmission in the dorsal hippocampus (DH) is necessary for drug context-induced reinstatement of cocaine- seeking behavior in an animal model of drug relapse. Furthermore, in vitro studies suggest that the Src family of tyrosine kinases critically regulates glutamatergic cellular functions within the DH. Thus, Src-family kinases in the DH may similarly control contextual cocaine- seeking behavior. To test this hypothesis, rats were trained to lever press for un-signaled cocaine infusions in a distinct context followed by extinction training in a different context. Cocaine-seeking behavior (non-reinforced active lever pressing) was then assessed in the previously cocaine-paired and extinction contexts after AP5 (N-methyl-D-aspartate glutamate (NMDA) receptor (NMDAR) antagonist; 0.25 or 2.5 mg/0.5 ml/hemisphere), PP2 (Src-family kinase inhibitor; 6.25 or 62.5 ng/0.5 ml/hemisphere), Ro25-6981 (NR2B subunit- containing NMDAR antagonist; 0.2 or 2 mg/0.5 ml/hemisphere), or vehicle administration into the DH. Administration of AP5, PP2, or Ro25-6981 into the DH dose-dependently impaired drug context-induced reinstatement of cocaine-seeking behavior relative to vehicle, without altering instrumental behavior in the extinction context or food-reinforced instrumental responding and general motor activity in control experiments.
    [Show full text]
  • Tinnitus Hopes Put to Sleep by Latest Auris Failure
    March 14, 2018 Tinnitus hopes put to sleep by latest Auris failure Madeleine Armstrong Ketamine is best known as a horse tranquiliser or a recreational drug, but it has also been proposed as a treatment for various disorders from depression to Alzheimer’s. Hopes of developing the drug in tinnitus have been dashed by the failure of Auris’s Keyzilen in a second phase III trial. As well as leaving Auris’s future looking bleak – Keyzilen is the second of its phase III candidates to flunk in four months – the setback could also be bad news for the sparse tinnitus pipeline. According to EvaluatePharma there is only one other candidate in active clinical development, Otonomy’s OTO-313, and this uses the same mechanism of action as Keyzilen (see table below). Tinnitus pipeline Generic Project Company Pharma class Trial(s) Notes name Phase III Auris Esketamine TACTT2 Keyzilen NMDA antagonist Failed Aug 2016 Medical hydrochloride (NCT01803646) TACTT3 Failed Mar 2018 (NCT02040194) Phase I OTO- Phase I/II trial to OTO-311 abandoned in Otonomy NMDA antagonist Gacyclidine 313 start H1 2019 favour of this formulation Preclinical Auris AM-102 Undisclosed - - Medical KCNQ2 Knopp Kv7 potassium - - Program Biosciences channel modulator Source: EvaluatePharma. Both projects are psychoactive drugs targeting the NMDA receptor. Tinnitus is commonly caused by loud noise and resulting damage to the sensory hair cells in the cochlea. Initial trauma to the inner ear has been shown to trigger excess production of glutamate, which leads to the hyperactivation of NMDA receptors and, in turn, cell death. Blocking the NMDA receptor could therefore have a protective effect – but it is unclear how this mechanism would work once the damage to hair cells had been done.
    [Show full text]
  • WO 2013/142184 Al 26 September 2013 (26.09.2013) P O P C T
    (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 WO 2013/142184 Al 26 September 2013 (26.09.2013) P O P C T (51) International Patent Classification: DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, A61K 33/16 (2006.01) A61K 31/7048 (2006.01) HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, A61K 33/14 (2006.01) A61K 31/70 (2006.01) KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, A61K 33/18 (2006.01) A61K 31/4196 (2006.01) ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, (21) International Application Number: RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, PCT/US20 13/030788 TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (22) International Filing Date: ZM, ZW. 13 March 2013 (13.03.2013) (84) Designated States (unless otherwise indicated, for every (25) Filing Language: English kind of regional protection available): ARIPO (BW, GH, GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, (26) Publication Language: English UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, (30) Priority Data: TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, 61/612,689 19 March 2012 (19.03.2012) US EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, (71) Applicant: YALE UNIVERSITY [US/US]; Two Whitney TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, Avenue, New Haven, CT 065 10 (US).
    [Show full text]
  • PHARMACEUTICAL APPENDIX to the TARIFF SCHEDULE 2 Table 1
    Harmonized Tariff Schedule of the United States (2020) Revision 19 Annotated for Statistical Reporting Purposes PHARMACEUTICAL APPENDIX TO THE HARMONIZED TARIFF SCHEDULE Harmonized Tariff Schedule of the United States (2020) Revision 19 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.
    [Show full text]
  • Rotenone-Induced Inner Retinal Degeneration Via Presynaptic
    www.nature.com/scientificreports OPEN Rotenone-induced inner retinal degeneration via presynaptic activation of voltage-dependent sodium and L-type calcium channels in rats Masaaki Sasaoka, Takashi Ota & Masaaki Kageyama* Rotenone, a mitochondrial complex I inhibitor, causes retinal degeneration via unknown mechanisms. To elucidate the molecular mechanisms of its action, we further characterized a rat model of rotenone- induced retinal degeneration. Intravitreal injection of rotenone (2 nmol/eye) damaged mainly the inner retinal layers, including cell loss in the ganglion cell and inner nuclear layers, which were very similar to those induced by 10 nmol/eye N-methyl-D-aspartate (NMDA). These morphological changes were accompanied by the reduced b-wave amplitude of electroretinogram, and increased immunostaining of 2,4-dinitrophenyl, an oxidative stress marker. Rotenone also downregulated expression of neuroflament light-chain gene (Nf) as a retinal ganglion cell (RGC) marker. This efect was prevented by simultaneous injection of rotenone with antioxidants or NMDA receptor antagonists. More importantly, voltage-dependent sodium and L-type calcium channel blockers and intracellular calcium signaling modulators remarkably suppressed rotenone-induced Nf downregulation, whereas none of these agents modifed NMDA-induced Nf downregulation. These results suggest that rotenone-induced inner retinal degeneration stems from indirect postsynaptic NMDA stimulation that is triggered by oxidative stress-mediated presynaptic intracellular calcium signaling via activation of voltage-dependent sodium and L-type calcium channels. Rotenone is a naturally occurring and broad-spectrum pesticide that inhibits the activity of NADH dehydroge- nase in the mitochondrial respiratory chain complex I1. Because of this unique biological activity, rotenone has been used as a versatile tool to study involvement of mitochondrial functions and oxidative stress in neuronal cell death.
    [Show full text]
  • A Radical Approach to Stroke Therapy
    Commentary A radical approach to stroke therapy James McCulloch* and Deborah Dewar Wellcome Surgical Institute and Hugh Fraser Neuroscience Laboratories, University of Glasgow, Glasgow G61 1QH, United Kingdom troke is a major cause of death and readily crosses the blood–brain barrier, (mitogen-activated protein kinases͞ Sdisability throughout the developed to augment endogenous brain ascorbic ERK1͞2). During ischemia, ERK1͞2 are world. Cerebrovascular disease ranks acid levels by up to 2 mM. However, in dephosphorylated, and there is a signif- third after cancer and heart disease as a the brain, ascorbic acid levels are heter- icant increase in ERK1͞2 phosphoryla- cause of death in the European Union ogeneous and highly compartmental- tion during reperfusion after forebrain and the U.S. The economic and social ized. In the rat, normal neuronal, glial, ischemia. Neurons and oligodendrocytes burdens of stroke are not consequences and cerebrospinal fluid levels of ascorbic at the margin of a focal ischemic lesion of mortality; they are imposed by the acid are Ϸ10 mM, 1 mM, and 0.5 mM, display increased MEK1͞2, indicating large majority of stroke patients who respectively (3). The antioxidant effects that this signaling pathway is activated survive but are physically and mentally of ascorbic acid at all of these sites within after ischemia and reperfusion in vivo disabled by stroke-induced brain dam- the brain could contribute to the efficacy (8). If MEK1͞2 is inhibited by the novel age. In the U.S., less than 2% of stroke of this agent in ischemia. Brain ascorbic agent, U0126, the extent of brain damage patients benefit from access to early acid levels are highly dynamic (although is reduced after either forebrain or focal thrombolysis, which removes the primary under rigorous homeostatic control), ischemia (2).
    [Show full text]
  • Chapter 1: Stroke and Neuroprotection 1 – 21
    DEVELOPMENT OF NOVEL THERAPEUTICS FOR STROKE: PRECLINICAL INVESTIGATIONS OF OSTEOPONTIN AND 3-IODOTHYRONAMINE By Kristian Paul Doyle A DISSERTATION Presented to the Department of Molecular Microbiology & Immunology at the Oregon Health & Science University in partial fulfillment of the requirements for the degree of Doctor of Philosophy 1 CONTENTS List of Figures v List of Tables ix Acknowledgements x Preface xi Abstract xii List of Abbreviations xv Chapter 1: Stroke and Neuroprotection 1 – 21 1.1 Introduction 2 1.2 Brief History of Stroke 2 1.3 Stroke Pathophysiology 4 1.4 Neuroprotection 17 1.5 Ischemic Preconditioning 19 1.6 Research Goal 21 Chapter 2: Osteopontin 22-86 2.1 An Introduction to OPN 23 2.2 The Structure of OPN 23 2.3 OPN, Integrins and Survival Signaling 25 2.4 OPN and Ischemic Injury 27 2.5 Preclinical Development of OPN 33 2.6 Optimizing Delivery 33 2 2.7 Improving the Potency of OPN 36 2.8 Identifying the Regions of OPN required for Neuroprotection 36 2.9 Hypothesis 37 2.10 Research Design 38 2.11 OPN has neuroprotective capability in vivo and in vitro 40 2.12 The mechanism of neuroprotection by OPN 51 2.13 OPN can be delivered to the brain by intranasal administration 56 2.14 Enhancing the neuroprotective capability of OPN 60 2.15 Peptides based on the N and C terminal fragment of thrombin cleaved OPN are neuroprotective 65 2.16 The C terminal peptide requires phosphorylation to be neuroprotective while the N terminal peptide does not require phosphorylation 70 2.17 Dose response and time window of NT 124-153 71 2.18
    [Show full text]
  • Alzheimer's Disease Clinical Trials
    Clinical Trial Perspective 5 Clinical Trial Perspective Alzheimer’s disease clinical trials: past failures and future opportunities Clin. Invest. (Lond.) Over a decade has elapsed since the US FDA has approved a medication for Alzheimer’s Roy Yaari*,1,2 & Ann Hake1,2 disease (AD) despite clinical trials of numerous agents over a wide array of mechanisms 1Eli Lilly & Company, Lilly Corporate including neurotransmitter modulation and disease modifying therapy targeting Center, Indianapolis, IN 46285, USA 2Indiana University School of Medicine, amyloid and tau. The failures of clinical trials in AD may be due to inadequate Department of Neurology, Indianapolis, understanding of mechanisms of action and/or poor target engagement; however, IN 46202, USA other factors could include inadequate study design, stage of AD along the continuum *Author for correspondence: studied, inclusion of participants without Alzheimer’s pathology into clinical trials Tel.: +1 317 651 6163 and limited power of endpoint measures. Future studies will need to carefully assess [email protected] these possible shortcomings in design of upcoming trials, especially as the field moves toward studies of disease modifying agents (as opposed to symptomatic treatment) of AD and to patients that are very early in the disease spectrum. Keywords: Alzheimer’s disease • Alzheimer’s disease biomarkers • amyloid • clinical trials • preclinical Alzheimer’s disease • tau US FDA approved medications continue to provide significant, but modest More than three decades ago, the choliner- symptomatic benefit[5–7] . gic hypothesis proposed that degeneration The compound memantine introduced a of cholinergic neurons in the basal fore- second mechanism for symptomatic treat- brain and the associated loss of cholinergic ment of AD into clinical practice.
    [Show full text]
  • TESE FINAL.Pdf
    FACULDADE DE MEDICINA DA UNIVERSIDADE DE COIMBRA TRABALHO FINAL DO 6º ANO MEDICO COM VISTA A ATRIBUIÇÃO DO GRAU DE MESTRE NO ÂMBITO DO CICLO DE ESTUDOS DO MESTRADO INTEGRADO EM MEDICINA ANA ALEXANDRA BRIGA CERQUEIRA ESTRATÉGIAS FARMACOLÓGICAS PARA AS ALTERAÇÕES PRECOCES DO COMPORTAMENTO NA DOENÇA DE ALZHEIMER TRABALHO DE REVISÃO ÁREA CIENTÍFICA DE FARMACOLOGIA TRABALHO REALIZADO SOBRE A ORIENTAÇÃO DE: PROFESSORA DOUTORA TICE DOS REIS ANASTÁCIO DE MACEDO MARÇO, 2009 ÍNDICE GERAL Agradecimentos.................................................................................................................3 Resumo..............................................................................................................................4 Abstract..............................................................................................................................6 Lista de Siglas....................................................................................................................8 Introdução........................................................................................................................11 Clínica e Diagnóstico……………...……………………………………………………11 Neuropatologia e Genética..............................................................................................15 Estratégias terapêuticas actuais...................................…………………………………23 Inibidores das colinesterases……………………………………………………23 Memantina……………………………………………………………………...27 Novas estratégias farmacológicas………………………………………………………30 Imunoterapia……………………………………………………………………34
    [Show full text]
  • Study Protocol 64565111EDI1002
    NCT03586830 Janssen Research & Development * Clinical Protocol Protocol Title A Randomized, Double-blind Placebo-controlled, Parallel-group, Multicenter, Dose- ranging Study to Evaluate the Safety and Efficacy of JNJ-64565111 in Severely Obese Subjects with Type 2 Diabetes Mellitus Short Title Evaluation of JNJ-64565111 in Severely Obese Subjects with Type 2 Diabetes Mellitus Protocol 64565111OBE2002; Phase 2b AMENDMENT 1 JNJ-64565111 *Janssen Research & Development is a global organization that operates through different legal entities in various countries. Therefore, the legal entity acting as the sponsor for Janssen Research & Development studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP; Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen Sciences Ireland UC; or Janssen Research & Development, LLC. The term “sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is identified on the Contact Information page that accompanies the protocol. US sites of this study will be conducted under US Food & Drug Administration IND regulations (21 CFR Part 312).] Status: Approved Date: 23 August 2018 Prepared by: Janssen Research & Development, LLC EDMS number: EDMS-ERI-156156741, 2.0 GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory requirements. Confidentiality Statement The information in this document contains trade secrets and commercial information that are privileged or confidential and may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed by them.
    [Show full text]