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The Development of Exogenous Anticonvulsants and Endogenous Uracil-Based Antiepileptic Agents

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The Development of Exogenous Anticonvulsants and Endogenous Uracil-Based Antiepileptic Agents THE DEVELOPMENT OF EXOGENOUS ANTICONVULSANTS AND ENDOGENOUS URACIL-BASED ANTIEPILEPTIC AGENTS by Sarah Ward Submitted in partial fulfillment of the requirements for the degree of Master of Science at Dalhousie University Halifax, Nova Scotia, Canada August 2011 © Copyright by Sarah Ward, 2011 DALHOUSIE UNIVERSITY DEPARTMENT OF CHEMISTRY The undersigned hereby certify that they have read and recommend to the Faculty of Graduate Studies for acceptance a thesis entitled “THE DEVELOPMENT OF EXOGENOUS ANTICONVULSANTS AND ENDOGENOUS URACIL-BASED ANTIEPILEPTIC AGENTS” by Sarah Ward in partial fulfilment of the requirements for the degree of Master of Science. Dated: August 19, 2011 Supervisor: _________________________________ Readers: _________________________________ _________________________________ _________________________________ ii DALHOUSIE UNIVERSITY DATE: August 19, 2011 AUTHOR: Sarah Ward TITLE: THE DEVELOPMENT OF EXOGENOUS ANTICONVULSANTS AND ENDOGENOUS URACIL-BASED ANTIEPILEPTIC AGENTS DEPARTMENT OR SCHOOL: Department of Chemistry DEGREE: MSc CONVOCATION: October YEAR: 2011 Permission is herewith granted to Dalhousie University to circulate and to have copied for non-commercial purposes, at its discretion, the above title upon the request of individuals or institutions. I understand that my thesis will be electronically available to the public. The author reserves other publication rights, and neither the thesis nor extensive extracts from it may be printed or otherwise reproduced without the author’s written permission. The author attests that permission has been obtained for the use of any copyrighted material appearing in the thesis (other than the brief excerpts requiring only proper acknowledgement in scholarly writing), and that all such use is clearly acknowledged. _______________________________ Signature of Author iii DEDICATION To those who live with epilepsy every day, especially KW—your perseverance and optimism have touched my life in a way I will never forget! iv TABLE OF CONTENTS List of Tables ..................................................................................................................... xi List of Figures................................................................................................................... xii List of Schemes................................................................................................................ xiv Abstract............................................................................................................................. xv List of Abbreviations Used .............................................................................................. xvi Acknowledgements........................................................................................................xviii Chapter 1: Introduction................................................................................................... 1 1.1 Epilepsy Overview......................................................................................... 1 1.1.1 The Definition and Etymology of Epilepsy............................................... 1 1.1.2 Nervous Tissue and the Pathology of Epilepsy ......................................... 1 1.1.3 Seizure Types............................................................................................. 4 1.1.3.1 Partial Seizures........................................................................................... 4 1.1.3.2 Generalized Seizures.................................................................................. 5 1.1.3.3 Unclassified Epileptic Seizures and Status Epilepticus............................. 6 1.1.4 Causes of Epilepsy..................................................................................... 7 1.2 Antiepileptic Drug Discovery........................................................................ 8 1.2.1 The History of Anticonvulsant Drug Discovery........................................ 8 1.2.2 The Modern Approach: Rational Antiepileptic Drug Design.................. 14 1.2.2.1 Discovery of a Lead Compound .............................................................. 16 1.2.2.1.1 Modulation of Voltage-Gated Ion Channels........................................ 17 1.2.2.1.2 Enhancement of GABA-Mediated Inhibition...................................... 19 1.2.2.1.3 Diminution of Glutamate-Mediated Excitation ................................... 20 v 1.2.2.2 Optimization of the Lead Compound ...................................................... 21 1.2.2.2.1 Pharmacodynamic Optimization........................................................... 21 1.2.2.2.2 Pharmacokinetic/Pharmaceutical Optimization, Lipinski’s Rules, and the Concept of a Prodrug ...................................................................... 22 1.2.2.3 Toxicity Testing....................................................................................... 24 1.2.2.4 Clinical Trials........................................................................................... 24 1.2.2.5 Additional Drug Criteria and Other Considerations ................................ 25 1.3 The Need for New Antiepileptic Drugs....................................................... 25 1.4 The Goal of this Thesis................................................................................ 28 Chapter 2: Project Descriptions.............................................................................. 29 2.1 Project 1: In Silico Search for Exogenous Anticonvulsants ........................ 29 2.1.1 The Sodium Channel Pharmacophore ..................................................... 29 2.1.2 Project 1 Outline: ..................................................................................... 30 2.2 Project 2: The Development of Uracils as Endogenous AEDs.................... 32 2.2.1 Uracil as a Lead Compound: Active Prodrug Rationale.......................... 32 2.2.2 Project 2 Outline ...................................................................................... 35 Chapter 3: Synthesis of Uracils .............................................................................. 39 3.1 Background Information.............................................................................. 39 3.2 Synthetic Approaches for Uracils ................................................................ 40 3.2.1 Synthetic Methods for Uracil Ring Formation ........................................ 40 3.2.2 Synthetic Methods for the Preparation of Substituted Uracils................. 42 3.2.2.1 The Synthesis of C5-Substituted Uracils.................................................. 42 3.2.2.2 The Synthesis of N-Substituted Uracils................................................... 44 3.3 Discussion of Uracil Analogue Synthesis.................................................... 47 vi 3.3.1 N1-Pyridinylmethyl Substituted Uracils .................................................. 47 3.3.1.1 The Synthesis of the 2-Pyridinylmethyl Uracil Derivatives.................... 48 3.3.1.2 The Synthesis of the 3-Pyridinylmethyl Uracil Derivatives.................... 51 3.3.2 The Benzylated Uracil Derivatives.......................................................... 56 3.3.2.1 The Synthesis of the N1-Monobenzylated Uracil Derivatives................. 56 3.3.2.2.1 The X-Ray Crystal Structures for Derivatives vi and 22a .................... 59 3.3.2.2 The Synthesis of the N1-Benzylated, N3-Alkylated Uracil Derivatives .. 61 Chapter 4: Experimental Procedures for the Synthesis of Uracils ......................... 62 4.1 General Methods.......................................................................................... 62 4.2 Experimental Procedures ............................................................................. 62 4.2.1 Synthesis of 5-bromo-1-(2-pyridinylmethyl)uracil (9a) .......................... 62 4.2.2 Synthesis of 5-methyl-1-(2-pyridinylmethyl)uracil (9b) ......................... 64 4.2.3 Synthesis of 1-(2-pyridinylmethyl)uracil (9c) ......................................... 65 4.2.4 Synthesis of 5-nitro-1-(2-pyridinylmethyl)uracil (9d)............................. 65 4.2.5 Synthesis of 5-iodo-1-(2-pyridinylmethyl)uracil (9e) ............................. 66 4.2.6 Synthesis of 5-trifluoromethyl-1-(2-pyridinylmethyl)uracil (9f)............. 67 4.2.7 Synthesis of 5-bromo-1-(3-pyridinylmethyl)uracil (10a) ........................ 68 4.2.8 Synthesis of 5-nitro-1-(3-pyridinylmethyl)uracil (10b)........................... 68 4.2.9 Synthesis of 5-trifluoromethyl-1-(3-pyridinylmethyl)uracil (10c) .......... 69 4.2.10 Synthesis of 5-iodo-1-(3-pyridinylmethyl)uracil (10d) and 5-iodo-1,3- di(3-pyridinylmethyl)uracil (11a) ............................................................. 70 4.2.11 Synthesis of 5-methyl-1,3-di(3-pyridinylmethyl)uracil (11b) ................. 71 4.2.12 Synthesis of 1,3-di(3-pyridinylmethyl)uracil (11c) ................................. 72 4.2.13 Synthesis of 5-bromo-1-(2-methylbenzyl)uracil (12a) ............................ 72 vii 4.2.14 Synthesis of 1-(2-methylbenzyl)uracil (12b)........................................... 73 4.2.15 Synthesis of 5-methyl-1-(2-methylbenzyl)uracil (12c) ........................... 74 4.2.16 Synthesis of 5-iodo-1-(2-methylbenzyl)uracil (12d) ............................... 74 4.2.17 Synthesis of 5-chloro-1-(2-methylbenzyl)uracil (12e) ............................ 75 4.2.18 Synthesis of 5-bromo-1-(3-methylbenzyl)uracil (13a) ............................ 76 4.2.19 Synthesis of
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