DOCSLIB.ORG

Ep 2522664 B1

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Ep 2522664 B1 (19) TZZ _T (11) EP 2 522 664 B1 (12) EUROPEAN PATENT SPECIFICATION (45) Date of publication and mention (51) Int Cl.: of the grant of the patent: C07D 401/04 (2006.01) C07D 413/04 (2006.01) 12.04.2017 Bulletin 2017/15 A61K 31/4545 (2006.01) (21) Application number: 12169655.3 (22) Date of filing: 29.06.2005 (54) Piperidine derivatives as NK1 antagonists Piperidinderivate als NK1-Antagonisten Dérivés de pipéridine en tant qu’ antagonistes NK1 (84) Designated Contracting States: • Wrobleski, Michelle Laci AT BE BG CH CY CZ DE DK EE ES FI FR GB GR Whitehouse Station, NJ New Jersey 08889 (US) HU IE IS IT LI LT LU MC NL PL PT RO SE SI SK TR • Rao, Ashwin U. Designated Extension States: Avenel, NJ New Jersey 07001 (US) AL BA HR LV MK YU • Wang, Cheng King of Prussia, PA Pennsylvania 19406 (US) (30) Priority: 01.07.2004 US 584502 P • Shah, Sapna S. Westampton, NJ New Jersey 08060 (US) (43) Date of publication of application: 14.11.2012 Bulletin 2012/46 (74) Representative: Simpson, Tobias Rutger Mathys & Squire LLP (62) Document number(s) of the earlier application(s) in The Shard accordance with Art. 76 EPC: 32 London Bridge Street 05787862.1 / 1 799 666 London SE1 9SG (GB) (73) Proprietor: OPKO Health, Inc. (56) References cited: Miami, FL 33137 (US) WO-A-03/042173 WO-A-03/051840 (72) Inventors: • WU X ET AL: "Stereoselective Transformation of • Palani, Anandan 2H-1,4-Oxazin-2-ones into 2,(2),5,5-Tri- and Bridgewater, NJ New Jersey 08807 (US) Tetrasubstituted Analogues of • Shih, Neng-Yang cis-5-Hydroxy-2-piperidinemethanol and Warren, NJ New Jersey 07059 (US) cis-5-Hydroxy-6-oxo-2-piperidi necarboxylic • Huang, Xianhai Acid", TETRAHEDRON, ELSEVIER SCIENCE Warren, NJ New Jersey 07059 (US) PUBLISHERS, AMSTERDAM, NL, vol. 56, no. 19, • Xiao, Dong May 2000 (2000-05), pages 3043-3051, Warren, NJ New Jersey 07059 (US) XP004198015, ISSN: 0040-4020 • Paliwal, Sunil • HARRISON T ET AL: "GEM- DISUBSTITUTED Monroe Township, NJ New Jersey 08831 (US) AMINO-ETHER BASED SUBSTANCE P • Tsui, Hon-Chung ANTAGONISTS", BIOORGANIC & MEDICINAL East Brunswick, NJ New Jersey 08816 (US) CHEMISTRY LETTERS, OXFORD, GB, vol. 4, no. 23, 1994, pages 2733-2734, XP000995889, ISSN: 0960-894X Note: Within nine months of the publication of the mention of the grant of the European patent in the European Patent Bulletin, any person may give notice to the European Patent Office of opposition to that patent, in accordance with the Implementing Regulations. Notice of opposition shall not be deemed to have been filed until the opposition fee has been paid. (Art. 99(1) European Patent Convention). EP 2 522 664 B1 Printed by Jouve, 75001 PARIS (FR) EP 2 522 664 B1 Description FIELD OF THE INVENTION 5 [0001] The present disclosure relates to novel neurokinin-1 (NK 1 or NK-1) receptor antagonists, pharmaceutical com- positions comprising such compounds, and methods of treatment using such compounds, to treat NK 1 receptor mediated diseases and conditions, including, for example, emesis, depression, anxiety and cough. BACKGROUND OF THE INVENTION 10 [0002] Tachykinins are peptide ligands for neurokinin receptors. Neurokinin receptors, such as NK1, NK2 and NK3, are involved in a variety of biological processes. They can be found in a mammal’s nervous and circulatory systems, as well as in peripheral tissues. Consequently, the modulation of these types of receptors has been studied to potentially treat or prevent various mammalian disease states. For instance, NK1 receptors have been reported to be involved in 15 microvascular leakage and mucus secretion. Representative types of neurokinin receptor antagonists and the disorders that can be treated with them include, for example, sleep, pain, migraine, emesis, nociception and inflammation; see, for example, U.S. 6,329,401, U.S. 5,760,018, U.S. 5,620,989, WO 95/19344, WO 94/13639, WO 94/10165, Wu et al., Tetrahedron, 56,6279-6290 (2000),Rombouts et al.,Tetrahedron, 59, 4721-4731 (2003), and Rogiers et al., Tetrahedron, 57, 8971-8981 (2001). 20 [0003] It would be beneficial to provide a NK 1 antagonist that is potent, selective, and possesses beneficial therapeutic and pharmacological properties, and good metabolic stability. It would further be beneficial to provide a NK 1 antagonist that is effective for treating a variety of physiological disorders, symptoms and diseases, while minimizing side effects. This invention provides such NK1 antagonists. [0004] WO 03/051840 discloses the use of pyrrolidine and piperidine derivatives as NK1 antagonists. 25 SUMMARY OF THE INVENTION [0005] According to the present invention, there is provided a compound as defined in the appended claims. Also provided are pharmaceutical compositions, compounds for use in methods of treatment, and kits as defined in the 30 appended claims. [0006] More generally, the present disclosure relates to a compound of Formula I: 35 40 or pharmaceutically acceptable salts and/or solvates thereof, wherein: R1 and R2 are each independently selected from the group consisting of H, alkyl, haloalkyl, alkyl substituted with 45 6 6 6 9 one or more hydroxyl groups, -CN, alkynyl, -N(R)2, -N(R )-S(O2)-alkyl, -N(R )-C(O)-N(R )2, -alkylene-CN, -cy- 5 9 cloalkylene-CN, -alkylene-O-alkyl, -C(O)-alkyl, -C(=N-OR )-alkyl, -C(O)-N(R )2, -C(O)-O-alkyl, -alkylene-C(O)-alkyl, 9 -alkylene-C(O)-O-alkyl, -alkylene-C(O)-N(R )2, 50 55 with the proviso that at least one of R 1 and R2 is -CN, 2 EP 2 522 664 B1 5 10 15 W is =C(R8)- or =N-; X is -C(O)- or -S(O2)-; 6 Y is selected from the group consisting of -CH 2-, -O-, and -N(R )-C(O)-, with the proviso that: 20 (a) the nitrogen atom of -N(R6)-C(O)- is bonded to X, and (b) if R1 and/or R2 is 25 30 and Y is -O-, X is not -S(O2)-; 7 6 Z is -C(R )2-, -N(R )-, or -O-; 3 5 35 R is selected from the group consisting of H, -CH2OR , and alkyl; R4 is selected from the group consisting of H, alkyl, cycloalkyl, heterocycloalkyl, heteroaryl, aryl, acyl, aroyl, alkylsulfonyl, and arylsulfonyl; R5 is H or alkyl; R6 is selected from the group consisting of H, alkyl, cycloalkyl, and aryl; 40 each R7 is independently H or alkyl; or each R7, together with the ring carbon to which they are shown attached, form a cycloalkylene ring; 8 6 R is selected from the group consisting of H, alkyl, alkyl substituted with one or more hydroxyl groups, -N(R )2, 6 6 6 6 -N(R )-S(O2)-alkyl, -N(R )-S(O2)-aryl, -N(R )-C(O)-alkyl, -N(R )-C(O)-aryl, alkylene-O-alkyl, and -CN; R9 is selected from the group consisting of H, alkyl, and aryl, or each R9, together with the nitrogen to which 45 they are shown attached, form a heterocycloalkyl ring; Ar1 and Ar 2 are each independently selected from the group consisting of unsubstituted aryl and aryl substituted with 0 to 3 substituents selected from the group consisting of halogen, alkyl, alkoxy, haloalkyl, haloalkoxy, -CN, -OH, and -NO2; n is 0, 1, or 2; and 50 m is 1, 2, or 3. [0007] In another instance, the present disclosure relates to a pharmaceutical composition comprising a therapeutically effective amount of at least one compound of Formula I, or a pharmaceutically acceptable salt and/or solvate thereof, and at least one pharmaceutically acceptable carrier. 55 [0008] In another instance, the present disclosure relates to a kit comprising two or more containers in a single package, wherein each container in the package comprises a pharmaceutical composition. At least one container of the package comprises an effective amount of the compound of Formula I, or a pharmaceutically acceptable salt and/or solvate thereof in a pharmaceutically acceptable carrier, and at least one other container of the package comprises another 3 EP 2 522 664 B1 therapeutic agent in a pharmaceutically acceptable carrier. The pharmaceutical compositions of the kit may be used in combination. [0009] In another instance, the present disclosure relates to a method for affecting an NK 1 receptor in a patient. The method comprises administering to the patient an effective amount of at least one compound of Formula I or a pharma- 5 ceutically acceptable salt and/or solvate thereof. [0010] In another instance, the present disclosure relates to a method for treating an NK 1 receptor mediated condition or disease (i.e., a disease associated with an NK 1 receptor, or a disease involving an NK 1 receptor in part of the disease process) in a patient in need of such treatment. The method comprises administering to the patient an effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt and/or solvate thereof. 10 [0011] Other features and advantages will be apparent from the following detailed description, and from the claims. DETAILED DESCRIPTION OF THE INVENTION [0012] In a first instance, the present disclosure relates to a compound of Formula I, or a solvate and/or salt thereof, 15 as described herein. Some of the compounds of Formula I are compounds of the present invention. Compounds of the present invention are defined in the appended claims. [0013] In yet another instance, the compounds of Formula I have the following structure IA: 20 25 30 3 [0014] In yet another instance of the compounds of Formula I, R is C1-6 alkyl; R4 is H; Ar1 is phenyl; 2 Ar is a phenyl substituted with 1 to 3 substituents selected from the group consisting of halogen, C 1-6 alkyl, C1-6 alkoxy, C1-6 haloalkyl, C1-6 haloalkoxy, -CN, and -NO2; and 35 n is 1.
Load more

Recommended publications
  • MASCC/ESMO ANTIEMETIC GUIDELINE 2016 with Updates in 2019
    1 ANTIEMETIC GUIDELINES: MASCC/ESMO MASCC/ESMO ANTIEMETIC GUIDELINE 2016 With Updates in 2019 Organizing and Overall Meeting Chairs: Matti Aapro, MD Richard J. Gralla, MD Jørn Herrstedt, MD, DMSci Alex Molassiotis, RN, PhD Fausto Roila, MD © Multinational Association of Supportive Care in CancerTM All rights reserved worldwide. 2 ANTIEMETIC GUIDELINES: MASCC/ESMO These slides are provided to all by the Multinational Association of Supportive Care in Cancer and can be used freely, provided no changes are made and the MASCC and ESMO logos, as well as date of the information are retained. For questions please contact: Matti Aapro at [email protected] Chair, MASCC Antiemetic Study Group or Alex Molassiotis at [email protected] Past Chair, MASCC Antiemetic Study Group 3 ANTIEMETIC GUIDELINES: MASCC/ESMO Consensus A few comments on this guideline set: • This set of guideline slides represents the latest edition of the guideline process. • This set of slides has been endorsed by the MASCC Antiemetic Guideline Committee and ESMO Guideline Committee. • The guidelines are based on the votes of the panel at the Copenhagen Consensus Conference on Antiemetic Therapy, June 2015. • Latest version: March 2016, with updates in 2019. 4 ANTIEMETIC GUIDELINES: MASCC/ESMO Changes: The Steering Committee has clarified some points: 2016: • A footnote clarified that aprepitant 165 mg is approved by regulatory authorities in some parts of the world ( although no randomised clinical trial has investigated this dose ). Thus use of aprepitant 80 mg in the delayed phase is only for those cases where aprepitant 125 mg is used on day 1. • A probable modification in pediatric guidelines based on the recent Cochrane meta-analysis is indicated.
    [Show full text]
  • Antiemetics/Antivertigo Agents
    Antiemetic Agents Therapeutic Class Review (TCR) May 1, 2019 No part of this publication may be reproduced or transmitted in any form or by any means, electronic or mechanical, including photocopying, recording, digital scanning, or via any information storage or retrieval system without the express written consent of Magellan Rx Management. All requests for permission should be mailed to: Magellan Rx Management Attention: Legal Department 6950 Columbia Gateway Drive Columbia, Maryland 21046 The materials contained herein represent the opinions of the collective authors and editors and should not be construed to be the official representation of any professional organization or group, any state Pharmacy and Therapeutics committee, any state Medicaid Agency, or any other clinical committee. This material is not intended to be relied upon as medical advice for specific medical cases and nothing contained herein should be relied upon by any patient, medical professional or layperson seeking information about a specific course of treatment for a specific medical condition. All readers of this material are responsible for independently obtaining medical advice and guidance from their own physician and/or other medical professional in regard to the best course of treatment for their specific medical condition. This publication, inclusive of all forms contained herein, is intended to be educational in nature and is intended to be used for informational purposes only. Send comments and suggestions to [email protected]. May 2019 Proprietary Information. Restricted Access – Do not disseminate or copy without approval. © 2004-2019 Magellan Rx Management. All Rights Reserved. 3 FDA-APPROVED INDICATIONS Drug Manufacturer Indication(s) NK1 receptor antagonists aprepitant capsules generic, Merck In combination with other antiemetic agents for: (Emend®)1 .
    [Show full text]
  • HHS Template for Reports, with Instructions
    Texas Vendor Drug Program 1.1 Drug Use Criteria: Substance P/Neurokinin1 Receptor Antagonists Publication History 1. Developed December 2003. 2. Revised September 2020; September 2018; September 2016; May 2015; August 2013; June 2013; September 2011; October 2009; February 2006; January 2006. Notes: Information on indications for use or diagnosis is assumed to be unavailable. All criteria may be applied retrospectively; prospective application is indicated with an asterisk [*]. The information contained is for the convenience of the public. The Texas Health and Human Services Commission is not responsible for any errors in transmission or any errors or omissions in the document. Medications listed in the tables and non-FDA approved indications included in these retrospective criteria are not indicative of Vendor Drug Program formulary coverage. Prepared by: • Drug Information Service, UT Health San Antonio. • The College of Pharmacy, The University of Texas at Austin. 1 1 Dosage [*] Current therapies for chemotherapy-induced nausea/vomiting (CINV) and post- operative nausea and vomiting (PONV) target corticosteroid, dopamine, and serotonin (5-HT3) receptors. In the central nervous system, tachykinins and neurokinins play a role in some autonomic reflexes and behaviors. Aprepitant is a selective human substance P/neurokinin 1 (NK1) antagonist with a high affinity for NK1 receptors and little, if any, attraction for corticosteroid, dopamine, or 5-HT3 receptors. Rolapitant (Varubi®), the newest substance P/NK1 antagonist, is FDA- approved to prevent delayed CINV with initial and repeat chemotherapy courses including, but not limited to, highly emetogenic chemotherapy in adults. Combination therapy including netupitant, a substance P/NK1 antagonist and palonosetron, a selective 5-HT3 receptor antagonist (Akynzeo®), is now available to prevent acute and delayed CINV with initial and repeat chemotherapy courses including, but not limited to, highly emetogenic chemotherapy in adults.
    [Show full text]
  • The Significance of NK1 Receptor Ligands and Their Application In
    pharmaceutics Review The Significance of NK1 Receptor Ligands and Their Application in Targeted Radionuclide Tumour Therapy Agnieszka Majkowska-Pilip * , Paweł Krzysztof Halik and Ewa Gniazdowska Centre of Radiochemistry and Nuclear Chemistry, Institute of Nuclear Chemistry and Technology, Dorodna 16, 03-195 Warsaw, Poland * Correspondence: [email protected]; Tel.: +48-22-504-10-11 Received: 7 June 2019; Accepted: 16 August 2019; Published: 1 September 2019 Abstract: To date, our understanding of the Substance P (SP) and neurokinin 1 receptor (NK1R) system shows intricate relations between human physiology and disease occurrence or progression. Within the oncological field, overexpression of NK1R and this SP/NK1R system have been implicated in cancer cell progression and poor overall prognosis. This review focuses on providing an update on the current state of knowledge around the wide spectrum of NK1R ligands and applications of radioligands as radiopharmaceuticals. In this review, data concerning both the chemical and biological aspects of peptide and nonpeptide ligands as agonists or antagonists in classical and nuclear medicine, are presented and discussed. However, the research presented here is primarily focused on NK1R nonpeptide antagonistic ligands and the potential application of SP/NK1R system in targeted radionuclide tumour therapy. Keywords: neurokinin 1 receptor; Substance P; SP analogues; NK1R antagonists; targeted therapy; radioligands; tumour therapy; PET imaging 1. Introduction Neurokinin 1 receptor (NK1R), also known as tachykinin receptor 1 (TACR1), belongs to the tachykinin receptor subfamily of G protein-coupled receptors (GPCRs), also called seven-transmembrane domain receptors (Figure1)[ 1–3]. The human NK1 receptor structure [4] is available in Protein Data Bank (6E59).
    [Show full text]
  • Quantitative Analysis of NK1 Receptor in the Human Brain Using PET with 18F-FE-SPA-RQ
    Quantitative Analysis of NK1 Receptor in the Human Brain Using PET with 18F-FE-SPA-RQ Masaki Okumura1,2, Ryosuke Arakawa1,2, Hiroshi Ito1, Chie Seki1, Hidehiko Takahashi1, Harumasa Takano1, Eisuke Haneda1,3, Ryuji Nakao4, Hidenori Suzuki3, Kazutoshi Suzuki4, Yoshiro Okubo2, and Tetsuya Suhara1 1Molecular Neuroimaging Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan; 2Department of Neuropsychiatry, Nippon Medical School, Tokyo, Japan; 3Department of Pharmacology, Nippon Medical School, Tokyo, Japan; and 4Molecular Probe Group, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba, Japan tachykinins—substance P (SP), neurokinin A, and neuro- 18F-fluoroethyl-SPA-RQ (18F-FE-SPA-RQ) was recently devel- kinin B—are known, and they share a consensus amino oped as a radioligand for the measurement of neurokinin 1 (NK1)re- acid sequence (-Phe-X-Gly-Leu-Met-NH ) in their car- 18 2 ceptor with PET. In this study, we used F-FE-SPA-RQ with PET to boxyl terminals (1–4). SP is a well-characterized neuro- visualize and quantify NK1 receptor in the human brain. Methods: PET scans were performed on 7 healthy men after intravenous injec- peptide, participating in neurotransmission by itself or 18 tion of F-FE-SPA-RQ. Binding potential (BPND) was calculated by synergistically with other neurotransmitters such as mono- theindirectkinetic,simplifiedreferencetissuemodel(SRTM),andra- amines, acetylcholine, and glutamate in nerve terminals. tio methods. The indirect kinetic method was used as the gold stan- Receptors for tachykinins—termed neurokinin 1 (NK1), dard method and was compared with the SRTM method, with scan NK , and NK receptors—have been identified (all are G times of 180, 270, and 330 min, and with the ratio method, with time 2 3 integration intervals of 120–180, 210–270, and 300–330 min.
    [Show full text]
  • Emerging Targets for Antidepressant Therapies Jeffrey J Rakofsky1, Paul E Holtzheimer2 and Charles B Nemeroff2
    Available online at www.sciencedirect.com Emerging targets for antidepressant therapies Jeffrey J Rakofsky1, Paul E Holtzheimer2 and Charles B Nemeroff2 Despite adequate antidepressant monotherapy, the majority of 70% of depressed patients have residual symptoms [3], depressed patients do not achieve remission. Even optimal and and, even with more aggressive therapies, 20% or more aggressive therapy leads to a substantial number of patients may show only a limited response [4]. Rather than being who show minimal and often only transient improvement. In the exception, recurrent episodes are the rule, and there order to address this substantial problem of treatment-resistant are few evidence-based approaches to help clinicians depression, a number of novel targets for antidepressant maintain a patient’s antidepressant response. Persistent therapy have emerged as a consequence of major advances in depression is associated with an increase in substance and the neurobiology of depression. Three major approaches to alcohol abuse, an increased risk for suicide and for car- uncover novel therapeutic interventions are: first, optimizing the diovascular disease. Thus, improved treatments for modulation of monoaminergic neurotransmission; second, depression are urgently needed. developing medications that act upon neurotransmitter systems other than monoaminergic circuits; and third, using Various forms of psychotherapy, pharmacotherapy, and focal brain stimulation to directly modulate neuronal activity. electroconvulsive therapy (ECT) are currently the most We review the most recent data on novel therapeutic commonly used antidepressant treatments. Serendipitous compounds and their antidepressant potential. These include discoveries and/or a limited understanding of the triple monoamine reuptake inhibitors, atypical antipsychotic neurobiology of depression which largely focused on the augmentation, and dopamine receptor agonists.
    [Show full text]
  • Download of These Slides, Please Direct Your Browser to the Following Web Address
    Clinical Roundtable Monograph Clinical Advances in Hematology & Oncology October 2015 Advances in the Management of Chemotherapy-Induced Nausea and Vomiting: New Data From Recent and Ongoing Trials Discussants Eric Roeland, MD Director of Clinical Research in Symptom Intervention Assistant Clinical Professor of Medicine University of California, San Diego Moores Cancer Center La Jolla, California Matti S. Aapro, MD Dean of the Multidisciplinary Oncology Institute A CME Activity Clinique de Genolier Approved for Genolier, Switzerland 1.25 AMA PRA Category 1 Credit(s) TM Lee S. Schwartzberg, MD Professor of Medicine Chief, Division of Hematology & Oncology Release Date: October 2015 The University of Tennessee Health Science Center Expiration Date: October 31, 2016 Memphis, Tennessee Estimated time to complete activity: 1.25 hours Project ID: 11026 Abstract: Chemotherapy-induced nausea and vomiting (CINV) is among the most feared and debilitating adverse events experienced by cancer patients. Left unaddressed, CINV symptoms not only decrease quality of life, but may also affect patients’ willingness to continue chemotherapy treatment. Detailed guidelines are available that outline best practices for prophylaxis of acute and delayed CINV. However, adherence to guideline recommendations continues to be suboptimal, and many patients still suffer unnecessarily from CINV. In addition, breakthrough/refractory CINV continues to present particular challenges. The development of effective CINV treatments with diverse mechanisms of action has expanded the options available for preventing symptoms. The US Food and Drug Administration has recently approved several new therapies for the management of CINV. NEPA is a fixed-dose combination of netupitant (300 mg) plus palonosetron (0.5 mg). In combination with dexamethasone, NEPA has demonstrated superior efficacy to palonosetron alone in patients receiving highly or moderately emetogenic chemotherapy.
    [Show full text]
  • Mechanisms of Nausea and Vomiting: Current Knowledge and Recent Advances in Intracellular Emetic Signaling Systems
    International Journal of Molecular Sciences Review Mechanisms of Nausea and Vomiting: Current Knowledge and Recent Advances in Intracellular Emetic Signaling Systems Weixia Zhong 1, Omar Shahbaz 2, Garrett Teskey 1, Abrianna Beever 3, Nala Kachour 3, Vishwanath Venketaraman 1,3 and Nissar A. Darmani 1,* 1 Department of Basic Medical Sciences, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, 309 East Second Street, Pomona, CA 91766, USA; [email protected] (W.Z.); [email protected] (G.T.); [email protected] (V.V.) 2 School of Medicine, Universidad Iberoamericana, Av. Francia 129, Santo Domingo 10203, Dominican Republic; [email protected] 3 Graduate College of Biomedical Sciences, Western University of Health Sciences, Pomona, CA 91766, USA; [email protected] (A.B.); [email protected] (N.K.) * Correspondence: [email protected]; Tel.: +1-909-469-5654 Abstract: Nausea and vomiting are common gastrointestinal complaints that can be triggered by diverse emetic stimuli through central and/or peripheral nervous systems. Both nausea and vomiting are considered as defense mechanisms when threatening toxins/drugs/bacteria/viruses/fungi enter the body either via the enteral (e.g., the gastrointestinal tract) or parenteral routes, including the blood, skin, and respiratory systems. While vomiting is the act of forceful removal of gastrointestinal contents, nausea is believed to be a subjective sensation that is more difficult to study in nonhuman species. In this review, the authors discuss the anatomical structures, neurotransmitters/mediators, Citation: Zhong, W.; Shahbaz, O.; and corresponding receptors, as well as intracellular emetic signaling pathways involved in the Teskey, G.; Beever, A.; Kachour, N.; processes of nausea and vomiting in diverse animal models as well as humans.
    [Show full text]
  • Neurokinin-1 (NK1) Receptor Antagonists and Combinations
    Therapeutic Class Overview Neurokinin-1 (NK1) Receptor Antagonists and Combinations Therapeutic Class Overview/Summary: This review will focus on miscellaneous antiemetics, which includes doxylamine succinate/pyridoxine ® hydrochloride (Diclegis ) as well as the neurokin-1 (NK1) receptor antagonists/combinations. NK1 antagonists are all Food and Drug Administration (FDA)-approved for the prevention of chemotherapy- 1-5 ® induced nausea and vomiting (CINV). Single-entity NK1 antagonists include: aprepitant (Emend ), its prodrug fosaprepitant dimeglumine (Emend®), and rolapitant hydrochloride (Varubi®). There is a single ® NK1 antagonist combination product currently available, netupitant/palonosetron (Akynzeo ). With this combination, netupitant, the NK1 antagonist is co-formulated with palonosetron, a serotonin type-3 (5- HT3) receptor antagonist. In addition to CINV, aprepitant is FDA-approved for the prevention of post- operative nausea and vomiting in adults.1-4 Differences in anti-emetic effect for the acute and delayed phases of CINV exist between NK1 antagonists and are summarized in Table 2. Doxylamine/pyridoxine is FDA-approved for the treatment of nausea and vomiting of pregnancy.5 As the pathophysiology of CINV is not completely understood, the exact mechanisms by which NK1 antagonists exert there antiemetic effects are not known. NK1 is a broadly distributed receptor located in both the central and peripheral nervous systems. One proposed mechanism of NK1 antagonists is by depressing the substance P mediated response in the central nevous system by blocking activation of NK1 in areas of the brain responsible for chemoreception. Decreased activation of NK1 by substance P reduces the emetic reflex. A second proposed mechanism is the blockade of peripheral NK1 receptors located on the vagal terminals of the gut.
    [Show full text]
  • Crystal Structure of the Human NK1 Tachykinin Receptor
    Crystal structure of the human NK1 tachykinin receptor Jie Yina, Karen Chapmana, Lindsay D. Clarka, Zhenhua Shaoa, Dominika Boreka, Qingping Xub, Junmei Wangc, and Daniel M. Rosenbauma,1 aDepartment of Biophysics, The University of Texas Southwestern Medical Center, Dallas, TX 75390; bGM/CA, Advanced Photon Source, Argonne National Laboratory, Argonne, IL 60439; and cSchool of Pharmacy, University of Pittsburgh, Pittsburgh, PA, 15261 Edited by Brian K. Kobilka, Stanford University School of Medicine, Stanford, CA, and approved November 9, 2018 (received for review July 25, 2018) The NK1 tachykinin G-protein–coupled receptor (GPCR) binds sub- and schizophrenia (8). While the receptor subtypes must share stance P, the first neuropeptide to be discovered in mammals. structural features for ligand recognition based on the fact that ThroughactivationofNK1R, substance P modulates a wide variety they bind tachykinins containing a conserved C-terminal peptide of physiological and disease processes including nociception, inflam- motif, it has nonetheless been possible to develop subtype- mation, and depression. Human NK1R (hNK1R) modulators have selective antagonists that discriminate between them (4). Be- shown promise in clinical trials for migraine, depression, and emesis. yond emesis and pain, selective NK1R antagonists have been However, the only currently approved drugs targeting hNK1Rare pursued in the clinic for IBS due to the proinflammatory role of inhibitors for chemotherapy-induced nausea and vomiting (CINV). substance P (1, 9). Selective NK2R antagonists have been pur- To better understand the molecular basis of ligand recognition sued for depression and anxiety disorders, as well as IBS (10). and selectivity, we solved the crystal structure of hNK1Rboundto Due to its interactions with dopaminergic neurons in the CNS, the inhibitor L760735, a close analog of the drug aprepitant.
    [Show full text]
  • Effects of NK1 and NMDA Receptor Antagonists on Severe Gagging Induced by Superior Laryngeal Nerve Stimulation in Rats
    1036614_英文誌16巻1号_01_2校_磯山 By IndesignCS3<P1> View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Kawasaki University of Medical Welfare Institutional Repository Kawasaki Journal of Medical Welfare Vol. 16, No. 1, 2010 1-8 Original Paper Effects of NK1 and NMDA Receptor Antagonists on Severe Gagging Induced by Superior Laryngeal Nerve Stimulation in Rats Ryuzo YAMAGATA* and Tomoshige KOGA** (Accepted Jun. 8, 2010) Key words: severe gagging, NK1 receptor, NMDA receptor, superior laryngeal nerve, decerebration Abstract Severe gagging, which is considered to be one of the emetic responses, prevents food bolus from being lodged in the pharyngo-laryngeal region. Little is known about the neuronal mechanism of severe gagging, because severe gagging is difficult to induce in animal experiments. In a recent study the authors reported that pulse train stimulation of the superior laryngeal nerve (SLN) at high frequency can be used to induce severe gagging in decerebrate rats. The present study was focused on the roles of NK1 and NMDA receptors in severe gagging and the influence that the receptor antagonists may exert on this process. Intravenous administration of WIN51708, NK1 receptor antagonist, significantly diminished the probability of the induction of severe gagging elicited by 3 sets of pulse train of the SLN at intervals of 1.7 sec (100Hz, 0.3ms, 50pulses, n=7). Similarly, MK-801, NMDA receptor antagonist, significantly diminished the probability of the induction of severe gagging (n=9). These results suggest that the neural circuits of severe gagging elicited by SLN stimulation could involve both NK1 and NMDA receptors.
    [Show full text]
  • Drug Class Review Monograph – GPI Class 50 – Antiemetics
    Formatted: Right Drug Class Review Monograph – GPI Class 50 – Antiemetics Review Time Frame: 02/2016 – 01/2017 Previous Class Review: 11/2016 Background: Antiemetic aAgents are drugs used for the prevention and treatment of nausea, vomiting, and motion sickness. There are five neurotransmitter receptor sites that are of primary importance in the vomiting reflex: muscarinic (MI), dopamine (D2), histamine (H1), 5-hydroxytryptamine (HT)-3 – serotonin, and neurokinin 1 (NK1) receptor – substance P. Anti-emetics are classified based upon their primary site of action, with some agents affecting multiple receptors. Classes of anti-emetics that antagonize the neurotransmitter receptors known to be involved in the physiology of nausea and vomiting include: • Anticholinergics (e.g., scopolamine) - antagonizes acetylcholine at muscarinic receptors and Formatted: Indent: Left: 0", Tab stops: 0.44", Left predominantly used as prophylaxis against motion sickness; • • Antihistamines (e.g., dimenhydrinate, meclizine) - antagonizes the effects of histamine on Formatted: Indent: Left: 0", Tab stops: 0.44", Left H1-receptors and primarily used for motion sickness; • • Dopamine rReceptor a Antagonists (e.g., prochlorperazine, chlorpromazine) - act predominantly by antagonizing D2-dopamine receptors in the area postrema of the midbrain; • • Serotonin rReceptor aAntagonists (5-HT3 receptor antagonists) - blocks the serotonin 5-HT3 Formatted: Font: Not Bold receptors which are found centrally in the chemoreceptor trigger zone and peripherally at Formatted: Font: Not Bold vagal nerve terminals in the intestines and antagonizes the effects of serotonin; Formatted: Font: Not Bold • • Neurokinin receptor antagonists - pPrevents acute and delayed vomiting by inhibiting the Formatted: Font: Not Bold substance P/NK1 receptor; augments the antiemetic activity of 5-HT3 receptor antagonists Formatted: Font: Not Bold and corticosteroids to inhibit acute and delayed phases of chemotherapy-induced emesis.
    [Show full text]