DOCSLIB.ORG

Title Page CEP-26401 (Irdabisant), a Potent and Selective Histamine H3 Receptor Antagonist/ Inverse Agonist with Cognition-Enhan

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Title Page CEP-26401 (Irdabisant), a Potent and Selective Histamine H3 Receptor Antagonist/ Inverse Agonist with Cognition-Enhan JPET Fast Forward. Published on October 14, 2011 as DOI: 10.1124/jpet.111.186585 JPET FastThis articleForward. has not Published been copyedited on and October formatted. 14,The final2011 version as DOI:10.1124/jpet.111.186585 may differ from this version. Title Page CEP-26401 (Irdabisant), a potent and selective histamine H3 receptor antagonist/ inverse agonist with cognition-enhancing and wake promoting activities Downloaded from Rita Raddatz, Robert L. Hudkins, Joanne R. Mathiasen*, John A. Gruner*, Dorothy G. Flood*, Lisa D. Aimone, Siyuan Le*, Hervé Schaffhauser*, Maciej Gasior*, Donna jpet.aspetjournals.org Bozyczko-Coyne, Michael J. Marino*, Mark A. Ator, Edward R. Bacon, John P. Mallamo and Michael Williams* at ASPET Journals on September 24, 2021 Discovery Research Cephalon, Inc. 145 Brandywine Parkway West Chester, PA 19380 USA Copyright 2011 by the American Society for Pharmacology and Experimental Therapeutics. JPET Fast Forward. Published on October 14, 2011 as DOI: 10.1124/jpet.111.186585 This article has not been copyedited and formatted. The final version may differ from this version. JPET #186585 2 Running Title H3 Receptor Antagonist CEP-26401 Corresponding author: Rita Raddatz Cephalon, Inc. 145 Brandywine Parkway West Chester, PA 19380 USA PHONE : (610) 738-6728 FAX: (610) 738-6305 Downloaded from [email protected] Text Pages: 48 Tables: 6 jpet.aspetjournals.org Figures: 7 References: 40 at ASPET Journals on September 24, 2021 Abstract (# of words): 240 Introduction (# of words): 490 Discussion (# of words): 1500 Abbreviations: H3R, histamine H3 receptor; CEP-26401, 6-{4-[3-((R)-2-methyl- pyrrolidin-1-yl)-propoxy]-phenyl}-2H-pyridazin-3-one HCl; ABT-239, 4-(2-{2-[(2R)-2- methyl-1-pyrrolidinyl]ethyl}-1-benzofuran-5-yl)benzonitrile (L) tartrate; RAMH, R-α- methylhistamine; GTPγS, guanosine 5`-(γ-thio)triphosphate; PPI, prepulse inhibition; [3H]NAMH, [3H]N-α-methylhistamine; RID, ratio of investigation duration; DTT, dithiothreitol; EEG, electroencephalographic; EMG, electromyographic; SWS, slow wave sleep; REMS, rapid eye movement sleep. Recommended section: Neuropharmacology JPET Fast Forward. Published on October 14, 2011 as DOI: 10.1124/jpet.111.186585 This article has not been copyedited and formatted. The final version may differ from this version. JPET #186585 3 Abstract CEP-26401 (Irdabisant) is a novel, potent histamine H3 receptor (H3R) antagonist/ inverse agonist with drug-like properties. High affinity of CEP-26401 for H3R was demonstrated in radioligand binding displacement assays in rat brain membranes (Ki = 2.7 ± 0.3 nM) and in recombinant rat and human H3R-expressing systems (Ki = 7.2 ± 0.4 nM, Ki = 2.0 ± 1.0 nM, respectively). CEP-26401 displayed potent antagonist and Downloaded from inverse agonist activities in [35S]GTPγS binding assays. Following oral dosing of CEP- 26401, occupancy of H3R was estimated by inhibition of ex vivo binding in rat cortical jpet.aspetjournals.org slices (OCC50 = 0.1 ± 0.003 mg/kg) and antagonism of the H3R agonist, R-α- methylhistamine (RAMH), -induced drinking response in the rat dipsogenia model was demonstrated in a similar dose range (ED50 = 0.06 mg/kg). CEP-26401 improved at ASPET Journals on September 24, 2021 performance in the rat social recognition model of short-term memory at doses of 0.01- 0.1 mg/kg p.o. and was wake-promoting at 3-30 mg/kg p.o. In DBA/2NCrl mice, CEP- 26401 at 10 and 30 mg/kg i.p. increased prepulse inhibition (PPI), while the antipsychotic risperidone was effective at 0.3 and 1 mg/kg i.p. Co-administration of CEP-26401 and risperidone at sub-efficacious doses (3 mg/kg i.p. and 0.1 mg/kg i.p., respectively) increased PPI. These results demonstrate potent behavioral effects of CEP-26401 in rodent models and suggest that this novel H3R antagonist may have therapeutic utility in the treatment of cognitive and attentional disorders. CEP-26401 may also have therapeutic utility in treating schizophrenia or as adjunctive therapy to approved antipsychotics. JPET Fast Forward. Published on October 14, 2011 as DOI: 10.1124/jpet.111.186585 This article has not been copyedited and formatted. The final version may differ from this version. JPET #186585 4 Introduction The CNS histaminergic system is involved in regulation of sleep-wake, attention and metabolic homeostasis via activation of a family of G-protein-coupled receptors (GPCRs) including H1, H2, H3 and H4 histamine receptors (Leurs et al., 2011). Of these, the H3 histamine receptor (H3R) was identified as a presynaptic autoreceptor modulating neuronal histamine release (Arrang et al., 1983). Subsequent studies demonstrated that H3R also functions as a heteroreceptor to modulate the release of other neurotransmitters Downloaded from associated with cognitive function and the regulation of sleep-wake, including acetylcholine, norepinephrine, dopamine, and serotonin (Esbenshade et al., 2008). jpet.aspetjournals.org The discovery of the H3R antagonists thioperamide and ciproxifan provided the pharmacological tools required for the exploration of the role of the H3R in CNS function. While active in multiple preclinical models, these early H3R antagonists were at ASPET Journals on September 24, 2021 limited as putative drug candidates due to poor target selectivity, lack of metabolic stability, potent hERG interactions, cytochrome P450 inhibition and poor brain penetration. Differences in pharmacology between the rodent and human H3Rs were also identified that hindered early drug discovery (Ireland-Denny et al., 2001). Considerable efforts in academia and industry resulted in the discovery of H3R antagonists / inverse agonists that have overcome many of these issues and provided tools to enhance understanding of H3R functions, with several compounds in clinical trials (Raddatz et al., 2010; Brioni et al., 2011; Berlin et al., 2011). The histaminergic system in the brain is active during wakefulness, and inhibitors of post-synaptic H1 histamine receptors are well established sedatives. The ability of H3R JPET Fast Forward. Published on October 14, 2011 as DOI: 10.1124/jpet.111.186585 This article has not been copyedited and formatted. The final version may differ from this version. JPET #186585 5 antagonists to increase activity in the brain histaminergic system and enhance vigilance and wakefulness has been demonstrated in multiple species (Parmentier et al., 2007). In addition to the effects of H3R antagonists on wake promotion in preclinical models, they are effective in decreasing episodes of cataplexy in a genetically narcoleptic Doberman Pinscher model (Bonaventure et al., 2007), suggesting the potential to treat multiple symptoms of narcolepsy. A number of H3R antagonists have also demonstrated efficacy across a broad range of preclinical models of cognitive function, including short- and Downloaded from long-term memory, working memory, spatial memory and sensorimotor gating (Esbenshade et al., 2008). H3R antagonists are currently being targeted for clinical use in jpet.aspetjournals.org the treatment of attention-deficit hyperactivity disorder (ADHD), Alzheimer’s disease (AD), schizophrenia and other disorders associated with cognitive impairment, as well as in the treatment of narcolepsy and sleep-wake disorders (Raddatz et al., 2010; Brioni et at ASPET Journals on September 24, 2021 al., 2011; Berlin et al., 2011; Leurs et al., 2011). In the present report, the pharmacological properties and behavioral effects of the novel H3R antagonist/ inverse agonist, CEP-26401 (6-{4-[3-((R)-2-methyl-pyrrolidin-1-yl)- propoxy]-phenyl}-2H-pyridazin-3-one; irdabisant; Hudkins et al., 2011) (Figure 1), are described. This selective, high affinity H3R antagonist potently enhanced short-term memory, improved PPI and demonstrated robust wake promotion in preclinical models, confirming the potential utility of H3R antagonists for the treatment of cognitive/ attentional disorders as well as sleep disorders. JPET Fast Forward. Published on October 14, 2011 as DOI: 10.1124/jpet.111.186585 This article has not been copyedited and formatted. The final version may differ from this version. JPET #186585 6 Methods Chemicals CEP-26401 and ABT-239 (Figure 1) were synthesized at Cephalon, Inc. (West Chester, PA) by methods previously described (Hudkins et al., 2011; Cowart et al., 2004). R-α- methylhistamine (RAMH), triprolidine, ranitidine hydrochloride, guanosine 5`-(γ- thio)triphosphate (GTPγS), thioperamide and ciproxifan were purchased from Sigma- Aldrich (St. Louis, MO). Clobenpropit and imetit dihydrobromide were purchased from Downloaded from Tocris (Ellisville, MO) and risperidone was purchased from Interchem (Paramus, NJ). [3H]N-α-methylhistamine ([3H]NAMH, 45-90 Ci/mmol), [3H]tiotidine (86 Ci/mmole), jpet.aspetjournals.org and [35S]GTPγS (1250 Ci/mmol) were purchased from PerkinElmer (Boston, MA). [3H]Pyrilamine (32 Ci/mmol) and [2,5-3H]histamine dihydrochloride ([3H]histamine, 30- 60 Ci/mmol) were purchased from GE Healthcare (Piscataway, NJ). at ASPET Journals on September 24, 2021 Receptor cloning and cell growth The cDNA encoding the 445-amino-acid splice variant of the rat histamine H3R (rH3R) (b.p. 338-1675 of GenBank accession no. NM_053506) was amplified from rat cDNA prepared from RNA isolated from thalamus, hypothalamus, striatum and prefrontal cortex. The sequence-verified cDNA was inserted into the pIRESneo3 vector (Clontech Laboratories, Inc., Palo Alto, CA) and the resulting construct was transfected into Chinese hamster ovary (CHO-A3) cells (cell line expressing mitochondrially
Load more

Recommended publications
  • 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]
  • 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]
  • (12) Patent Application Publication (10) Pub. No.: US 2010/0221245 A1 Kunin (43) Pub
    US 2010O221245A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2010/0221245 A1 Kunin (43) Pub. Date: Sep. 2, 2010 (54) TOPICAL SKIN CARE COMPOSITION Publication Classification (51) Int. Cl. (76) Inventor: Audrey Kunin, Mission Hills, KS A 6LX 39/395 (2006.01) (US) A6II 3L/235 (2006.01) A638/16 (2006.01) Correspondence Address: (52) U.S. Cl. ......................... 424/133.1: 514/533: 514/12 HUSCH BLACKWELL SANDERS LLP (57) ABSTRACT 4801 Main Street, Suite 1000 - KANSAS CITY, MO 64112 (US) The present invention is directed to a topical skin care com position. The composition has the unique ability to treat acne without drying out the user's skin. In particular, the compo (21) Appl. No.: 12/395,251 sition includes a base, an antibacterial agent, at least one anti-inflammatory agent, and at least one antioxidant. The (22) Filed: Feb. 27, 2009 antibacterial agent may be benzoyl peroxide. US 2010/0221 245 A1 Sep. 2, 2010 TOPCAL SKIN CARE COMPOSITION stay of acne treatment since the 1950s. Skin irritation is the most common side effect of benzoyl peroxide and other anti BACKGROUND OF THE INVENTION biotic usage. Some treatments can be severe and can leave the 0001. The present invention generally relates to composi user's skin excessively dry. Excessive use of some acne prod tions and methods for producing topical skin care. Acne Vul ucts may cause redness, dryness of the face, and can actually garis, or acne, is a common skin disease that is prevalent in lead to more acne. Therefore, it would be beneficial to provide teenagers and young adults.
    [Show full text]
  • Ciproxifan, a Histamine H3 Receptor Antagonist, Reversibly Inhibits Monoamine Oxidase a and B Received: 05 September 2016 S
    www.nature.com/scientificreports OPEN Ciproxifan, a histamine H3 receptor antagonist, reversibly inhibits monoamine oxidase A and B Received: 05 September 2016 S. Hagenow1, A. Stasiak2, R. R. Ramsay3 & H. Stark1 Accepted: 07 December 2016 Ciproxifan is a well-investigated histamine H receptor (H3R) inverse agonist/antagonist, showing Published: 13 January 2017 3 an exclusively high species-specific affinity at rodent compared to human H3R. It is well studied as reference compound for H3R in rodent models for neurological diseases connected with neurotransmitter dysregulation, e.g. attention deficit hyperactivity disorder or Alzheimer’s disease. In a screening for potential monoamine oxidase A and B inhibition ciproxifan showed efficacy on both enzyme isoforms. Further characterization of ciproxifan revealed IC50 values in a micromolar concentration range for human and rat monoamine oxidases with slight preference for monoamine oxidase B in both species. The inhibition by ciproxifan was reversible for both human isoforms. Regarding inhibitory potency of ciproxifan on rat brain MAO, these findings should be considered, when using high doses in rat models for neurological diseases. As the H3R and monoamine oxidases are all capable of affecting neurotransmitter modulation in brain, we consider dual targeting ligands as interesting approach for treatment of neurological disorders. Since ciproxifan shows only moderate activity at human targets, further investigations in animals are not of primary interest. On the other hand, it may serve as starting point for the development of dual targeting ligands. Ciproxifan (cyclopropyl 4-(3-(1H-imidazol-4-yl)propyloxy)phenyl methanone) is a well characterized species-specific histamine 3H receptor (H3R) inverse agonist/antagonist (Fig.
    [Show full text]
  • International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors
    1521-0081/67/3/601–655$25.00 http://dx.doi.org/10.1124/pr.114.010249 PHARMACOLOGICAL REVIEWS Pharmacol Rev 67:601–655, July 2015 Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics ASSOCIATE EDITOR: ELIOT H. OHLSTEIN International Union of Basic and Clinical Pharmacology. XCVIII. Histamine Receptors Pertti Panula, Paul L. Chazot, Marlon Cowart, Ralf Gutzmer, Rob Leurs, Wai L. S. Liu, Holger Stark, Robin L. Thurmond, and Helmut L. Haas Department of Anatomy, and Neuroscience Center, University of Helsinki, Finland (P.P.); School of Biological and Biomedical Sciences, University of Durham, United Kingdom (P.L.C.); AbbVie, Inc. North Chicago, Illinois (M.C.); Department of Dermatology and Allergy, Hannover Medical School, Hannover, Germany (R.G.); Department of Medicinal Chemistry, Amsterdam Institute of Molecules, Medicines and Systems, VU University Amsterdam, The Netherlands (R.L.); Ziarco Pharma Limited, Canterbury, United Kingdom (W.L.S.L.); Institute of Pharmaceutical and Medical Chemistry (H.S.) and Institute of Neurophysiology, Medical Faculty (H.L.H.), Heinrich-Heine-University Duesseldorf, Germany; and Janssen Research & Development, LLC, San Diego, California (R.L.T.) Abstract ....................................................................................602 Downloaded from I. Introduction and Historical Perspective .....................................................602 II. Histamine H1 Receptor . ..................................................................604 A. Receptor Structure
    [Show full text]
  • Identification and Analysis of Hepatitis C Virus NS3 Helicase Inhibitors Using Nucleic Acid Binding Assays Sourav Mukherjee1, Alicia M
    Published online 27 June 2012 Nucleic Acids Research, 2012, Vol. 40, No. 17 8607–8621 doi:10.1093/nar/gks623 Identification and analysis of hepatitis C virus NS3 helicase inhibitors using nucleic acid binding assays Sourav Mukherjee1, Alicia M. Hanson1, William R. Shadrick1, Jean Ndjomou1, Noreena L. Sweeney1, John J. Hernandez1, Diana Bartczak1, Kelin Li2, Kevin J. Frankowski2, Julie A. Heck3, Leggy A. Arnold1, Frank J. Schoenen2 and David N. Frick1,* 1Department of Chemistry and Biochemistry, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, 2University of Kansas Specialized Chemistry Center, University of Kansas, 2034 Becker Dr., Lawrence, KS 66047 and 3Department of Biochemistry and Molecular Biology, New York Medical College, Valhalla, NY 10595, USA Received March 26, 2012; Revised May 30, 2012; Accepted June 4, 2012 Downloaded from ABSTRACT INTRODUCTION Typical assays used to discover and analyze small All cells and viruses need helicases to read, replicate and molecules that inhibit the hepatitis C virus (HCV) repair their genomes. Cellular organisms encode NS3 helicase yield few hits and are often con- numerous specialized helicases that unwind DNA, RNA http://nar.oxfordjournals.org/ founded by compound interference. Oligonucleotide or displace nucleic acid binding proteins in reactions binding assays are examined here as an alternative. fuelled by ATP hydrolysis. Small molecules that inhibit After comparing fluorescence polarization (FP), helicases would therefore be valuable as molecular homogeneous time-resolved fluorescence (HTRFÕ; probes to understand the biological role of a particular Cisbio) and AlphaScreenÕ (Perkin Elmer) assays, helicase, or as antibiotic or antiviral drugs (1,2). For an FP-based assay was chosen to screen Sigma’s example, several compounds that inhibit a helicase Library of Pharmacologically Active Compounds encoded by herpes simplex virus (HSV) are potent drugs in animal models (3,4).
    [Show full text]
  • Pitolisant | Medchemexpress
    Inhibitors Product Data Sheet Pitolisant • Agonists Cat. No.: HY-12199 CAS No.: 362665-56-3 Molecular Formula: C₁₇H₂₆ClNO • Molecular Weight: 295.85 Screening Libraries Target: Histamine Receptor Pathway: GPCR/G Protein; Immunology/Inflammation; Neuronal Signaling Storage: Pure form -20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month SOLVENT & SOLUBILITY In Vitro DMSO : 100 mg/mL (338.01 mM; Need ultrasonic) Mass Solvent 1 mg 5 mg 10 mg Concentration Preparing 1 mM 3.3801 mL 16.9005 mL 33.8009 mL Stock Solutions 5 mM 0.6760 mL 3.3801 mL 6.7602 mL 10 mM 0.3380 mL 1.6900 mL 3.3801 mL Please refer to the solubility information to select the appropriate solvent. In Vivo 1. Add each solvent one by one: 10% DMSO >> 40% PEG300 >> 5% Tween-80 >> 45% saline Solubility: ≥ 2.5 mg/mL (8.45 mM); Clear solution 2. Add each solvent one by one: 10% DMSO >> 90% (20% SBE-β-CD in saline) Solubility: ≥ 2.5 mg/mL (8.45 mM); Clear solution 3. Add each solvent one by one: 10% DMSO >> 90% corn oil Solubility: ≥ 2.5 mg/mL (8.45 mM); Clear solution BIOLOGICAL ACTIVITY Description Pitolisant is a potent and selective nonimidazole inverse agonist at the recombinant human histamine H3 receptor (Ki=0.16 nM). IC₅₀ & Target Ki: 0.16 nM (H3 receptor)[1] EC50: 1.5 nM (H3 receptor)[1] In Vitro On the stimulation of guanosine 5′-O-(3-[35S]thio)triphosphate binding to this receptor, Pitolisant (BF2.649) behaves as a Page 1 of 3 www.MedChemExpress.com competitive antagonist with a Ki value of 0.16 nM and as an inverse agonist with an EC50 value of 1.5 nM and an intrinsic activity ~50% higher than that of ciproxifan.
    [Show full text]
  • Histamine H Receptor Antagonists
    Histamine H3 Receptor Antagonists from Bench to Bedside Holger Stark XVIIIth Summer School on Medicinal Chemistry Rio de Janeiro/Brazil, January 23-27, 2012 Institut für Pharmazeutische Chemie Biozentrum, Johann Wolfgang Goethe-Universität E-Mail: [email protected] H. Stark Stark-Lab Biogenic Amines Lipids Dopamine Histamine NMDA Sphingosine AA 1 Content Introduction histamine receptors . Subtypes . Functions Histamine H3 receptor antagonists . From imidazole to non-imidazole compounds . Pharmacological tools . Clinical candidates – clinical trials Summary 3 NH2 HN The Magnificent Seven N Four histamine receptor subtypes (H1 –H4) Original source: 七人の侍 Shichinin no samurai 2 NH2 HN Histaminergic System N Histamine . Modulator of (patho)physiological effects in CNS and periphery Tuberomammilary nucleus Histamine receptors GPCR Class A H1 H2 H3 H4 Allergic reactions Gastric Neurotransmission Inflammatory Sleep / wake cycle acid secretion processes 5 Schematic Histaminergic Innervation L-Histidine H3 Heteroreceptors (ACh, DA, 5-HT, NA, NANC ...) - Glia cells Histamine Gi/o - N-Methyl- H3 histamine Histamine HMT H4 Modulation of H H1 2 energy metabolism blood circulation IP3 DAG cAMP 6 sleep / waking state 3 Therapeutic Targets of Histamine H3 Receptor Antagonists Schizophrenia, depression Epilepsy Neuropathic pain Sleep-wake disorders hH R (narcolepsy) 3 Cancer Cognition disorders Allergy (Alzheimer´s D, ADHD) Migraine Obesity 7 Histamine H3 Receptor Antagonists In vitro In vivo S Ki ED50 p.o. [nM] [mg/kg] N N H N Thioperamide 2.2 1 N H N O N FUB 465 580 0.26 H N O N 19 (>10) (protean H Proxyfan O agonist) N O inverse N Ciproxifan 0.5 0.14 agonist H 8 4 Synthesis of Keto Derivatives 4-(3-Phenoxypropyl)-1H-imidazole Structure O C R1 Mitsunobu O N reaction OH + + HO H C 1 2 R N R CPh N O 3 R2 N 4/5 steps H+ H O NaH NOH C C 1 R1 R N OH N + F O 2 R2 R N N H CPh3 1 R CH3 CH3 CH3 (CH2)1-5-H CH3 CH3 C2H5 Ph 2 etc.
    [Show full text]
  • New Use of Glutaminyl Cyclase Inhibitors
    (19) TZZ _Z T (11) EP 2 481 408 A2 (12) EUROPEAN PATENT APPLICATION (43) Date of publication: (51) Int Cl.: 01.08.2012 Bulletin 2012/31 A61K 31/4164 (2006.01) A61K 31/4184 (2006.01) A61K 31/422 (2006.01) A61K 31/4178 (2006.01) (2006.01) (2006.01) (21) Application number: 11192085.6 A61K 31/433 A61K 31/5415 A61K 31/517 (2006.01) A61P 25/28 (2006.01) (2006.01) (2006.01) (22) Date of filing: 28.02.2008 A61P 29/00 A61P 3/08 A61K 45/06 (2006.01) (84) Designated Contracting States: • Hoffmann, Torsten AT BE BG CH CY CZ DE DK EE ES FI FR GB GR 06114 Halle / Saale (DE) HR HU IE IS IT LI LT LU LV MC MT NL NO PL PT • Cynis, Holger RO SE SI SK TR 06110 Halle / Saale (DE) • Demuth, Hans-Ulrich (30) Priority: 01.03.2007 US 892265 P 06120 Halle / Saale (DE) 14.03.2007 US 685881 (74) Representative: Hoffmann, Matthias et al (62) Document number(s) of the earlier application(s) in Maikowski & Ninnemann accordance with Art. 76 EPC: Patentanwälte 08717208.6 / 2 117 540 Kurfürstendamm 54-55 10707 Berlin (DE) (71) Applicant: Probiodrug AG 06120 Halle/Saale (DE) Remarks: This application was filed on 06-12-2011 as a (72) Inventors: divisional application to the application mentioned • Schilling, Stephan under INID code 62. 06130 Halle / Saale (DE) (54) New use of glutaminyl cyclase inhibitors (57) The present invention relates in general to an c. fibrosis, e.g. lung fibrosis, liver fibrosis, renal fibrosis, inhibitor of a glutaminyl peptide cyclotransferase, and d.
    [Show full text]
  • EVALUATION of ANTIHISTAMINES for in Vitro ANTIMALARIAL ACTIVITY AGAINST Plasmodium Falciparum
    EVALUATION OF ANTIHISTAMINES FOR in vitro ANTIMALARIAL ACTIVITY AGAINST Plasmodium falciparum SHAIK ANEESA A full thesis submitted in fulfilment of the requirements for the degree of Magister Pharmaceuticiae in the Faculty of Natural Sciences, School of Pharmacy, University of the Western Cape Supervisor: Dr. Henry Martin John Leng January 2011 I #75-0"1 Plasmodium falciparum Antihistamines Chloroquine resistance Synergism Cyproheptadine Ketotifen Chlorpheniramine H3 antagonists Morphology Haemoglobin II #!*02'-, I declare that Evaluation of Antihistamines for in vitro Antimalarial Activity against Plasmodium falciparum is my own work, that it has not been submitted for any degree or examination in any other university, and that all the sources I have used or quoted have been indicated and acknowledged by complete references. Full name.................................... Date.................................. Signed......................................... III ABSTRACT Evaluation of Antihistamines for in vitro Antimalarial Activity against Plasmodium falciparum Aneesa Shaik M. Pharm thesis, School of Pharmacy, University of the Western Cape, Bellville, South Africa January 2011 The declining efficacy of antimalarial drugs against resistant Plasmodium falciparum strains in several endemic regions has amplified the world’s burden of neglected diseases. This has highlighted the need for alternate strategies for chemotherapy and chemoprophylaxis. Since malaria is prevalent primarily in third world countries, it is critical for novel therapies
    [Show full text]
  • Pitolisant and Other Histamine-3 Receptor Antagonists—An Update on Therapeutic Potentials and Clinical Prospects
    medicines Review Pitolisant and Other Histamine-3 Receptor Antagonists—An Update on Therapeutic Potentials and Clinical Prospects Victoria Harwell and Pius S. Fasinu * Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, Campbell University, Buies Creek, NC 27501, USA; [email protected] * Correspondence: [email protected] Received: 28 July 2020; Accepted: 27 August 2020; Published: 1 September 2020 Abstract: Background: Besides its well-known role as a peripheral chemical mediator of immune, vascular, and cellular responses, histamine plays major roles in the central nervous system, particularly in the mediation of arousal and cognition-enhancement. These central effects are mediated by the histamine-3 auto receptors, the modulation of which is thought to be beneficial for the treatment of disorders that impair cognition or manifest with excessive daytime sleepiness. Methods: A database search of PubMed, Google Scholar, and clinicaltrials.gov was performed in June 2020. Full-text articles were screened and reviewed to provide an update on pitolisant and other histamine-3 receptor antagonists. Results: A new class of drugs—histamine-3 receptor antagonists—has emerged with the approval of pitolisant for the treatment of narcolepsy with or without cataplexy. At the recommended dose, pitolisant is well tolerated and effective. It has also been evaluated for potential therapeutic benefit in Parkinson disease, epilepsy, attention deficit hyperactivity disorder, Alzheimer’s disease, and dementia. Limited
    [Show full text]
  • The Histamine H3 Receptor: Structure, Pharmacology and Function
    Molecular Pharmacology Fast Forward. Published on August 25, 2016 as DOI: 10.1124/mol.116.104752 This article has not been copyedited and formatted. The final version may differ from this version. MOL #104752 The histamine H3 receptor: structure, pharmacology and function Gustavo Nieto-Alamilla, Ricardo Márquez-Gómez, Ana-Maricela García-Gálvez, Guadalupe-Elide Morales-Figueroa and José-Antonio Arias-Montaño Downloaded from Departamento de Fisiología, Biofísica y Neurociencias, molpharm.aspetjournals.org Centro de Investigación y de Estudios Avanzados (Cinvestav-IPN), Av. IPN 2508, Zacatenco, 07360 México, D.F., México at ASPET Journals on September 29, 2021 Running title: The histamine H3 receptor Correspondence to: Dr. José-Antonio Arias-Montaño Departamento de Fisiología, Biofísica y Neurociencias Cinvestav-IPN Av. IPN 2508, Zacatenco 07360 México, D.F., México. Tel. (+5255) 5747 3964 Fax. (+5255) 5747 3754 Email [email protected] 1 Molecular Pharmacology Fast Forward. Published on August 25, 2016 as DOI: 10.1124/mol.116.104752 This article has not been copyedited and formatted. The final version may differ from this version. MOL #104752 Text pages 66 Number of tables 3 Figures 7 References 256 Words in abstract 168 Downloaded from Words in introduction 141 Words in main text 9494 molpharm.aspetjournals.org at ASPET Journals on September 29, 2021 2 Molecular Pharmacology Fast Forward. Published on August 25, 2016 as DOI: 10.1124/mol.116.104752 This article has not been copyedited and formatted. The final version may differ
    [Show full text]