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Design, Synthesis and Evaluation of 5-Ht7 Antagonists for the Treatment of Inflammatory Bowel Disease

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Design, Synthesis and Evaluation of 5-Ht7 Antagonists for the Treatment of Inflammatory Bowel Disease DESIGN, SYNTHESIS AND EVALUATION OF 5-HT7 ANTAGONISTS FOR THE TREATMENT OF INFLAMMATORY BOWEL DISEASE _________________________________________________________ A Dissertation Submitted to the Temple University Graduate Board _________________________________________________________ In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy _________________________________________________________ By Kevin M. Blattner December 2018 Examining Committee Members: Dr. Benjamin E. Blass, Advisory Chair, Department of Pharmaceutical Sciences Dr. Daniel J. Canney, Department of Pharmaceutical Sciences Dr. Wayne E. Childers, Department of Pharmaceutical Sciences Dr. Sara Ward, External Member, Temple University Lewis Katz School of Medicine ABSTRACT The 5-HT7 receptor is the most recently discovered 5-HT receptor subtype. 5-HT7 is a GPCR that exhibits a regulatory role in many biological functions in both the central nervous system (CNS) and the periphery. Recent literature has demonstrated a connection between the 5- HT7 receptor and Inflammatory Bowel Disease (IBD) progression. IBD is a devastating disease that affects 1.4 million Americans. Patients suffer from life altering symptoms as a result of severe, chronic inflammation of the gastrointestinal tract. Current treatments mitigate symptoms with no effect on disease progression. Targeting the 5-HT7 receptor as a novel treatment option is a viable medicinal chemistry project that could result in a therapy capable of providing relief to IBD patients. A novel series of butyrolactones were discovered during a prior thesis project completed by Dr. Rong Gao at Temple University’s School of Pharmacy. Broad screening indicated that many of the compounds within this series were potent binders of the 5-HT7 receptor. These results led to the initiation of a medicinal chemistry program aimed at the development of this series with the intent to identify novel 5-HT7 receptor antagonists that are suitable for pre-clinical and clinical evaluation for the treatment of IBD. Medicinal chemistry strategies were utilized in order to optimize each structural aspect of the butyrolactone pharmacophore. This required the preparation of several small series of compounds wherein one structural feature was systematically changed while the remaining features were held constant. The particular properties that were studied for optimization included 5-HT7 affinity, subtype selectivity, liver microsomes stability (mouse and human), and the topological polar surface area (to minimize CNS penetration). Implementing these strategies led to the identification of potent 5-HT7 antagonists, some of which exhibited excellent subtype selectivity and improved mouse liver microsome stability. Two analogs, 170073 and 230168, were chosen for further study. Both analogs exhibited adequate in vivo pharmacokinetic profiles capable of supporting efficacy in an in vivo setting. 170073 distributed rapidly and ii extensively into brain tissue, while 230168 moderately distributed into brain tissue. Moving forward, reducing CNS penetration will become a top priority. These two compounds were examined in the DSS induced mouse model of IBD and both exhibited efficacy. Specifically in the acute DSS model of colitis, 170073 and 230168 significantly lowered the disease activity index, mitigated histological damage and reduced the production of proinflammatory cytokines. In addition, 170073 demonstrated efficacy in the chronic DSS model of colitis. 230168 has yet to be tested in the chronic model. The results of this dissertation support the validity of this project and the use of 5-HT7 antagonists as a potential novel treatment option for IBD. iii TABLE OF CONTENTS PAGE ABSTRACT ................................................................................................................................. II LIST OF FIGURES .................................................................................................................. IX LIST OF TABLES .................................................................................................................. XII LIST OF SCHEMES ............................................................................................................. XIV CHAPTER 1 SEROTONIN: A DIVERSE SIGNALING HORMONE ................................................... 1 1.1 A Brief Historical Perspective .......................................................................................... 1 1.2 5-HT: Biological Synthesis and General Functions ....................................................... 2 1.3 A Large Diverse Family of 5-HT Receptor Subtypes ................................................... 3 CHAPTER 2 THE 5-HT7 SUBTYPE: BIOCHEMISTRY, LIGANDS AND SIGNALING ............... 9 2.1 Structure and Distribution ................................................................................................. 9 2.2 Signaling and Cellular Mechanisms ............................................................................... 11 2.3 Constitutive Activity, G-Protein Interaction and Dimerization .................................. 15 2.4 Ligands and Long-chained Arylpiperazines ................................................................. 17 2.5 Effects on other Neurotransmitters ................................................................................. 23 CHAPTER 3 PHYSIOLOGICAL FUNCTION AND THERAPEUTIC POTENTIAL OF 5-HT7 RECEPTORS ............................................................................................................................. 26 iv 3.1 Circadian Rhythm and Sleep ........................................................................................... 26 3.2 Depression ......................................................................................................................... 28 3.3 Thermoregulation ............................................................................................................. 31 3.4 Anxiety ............................................................................................................................... 32 3.5 Stress and Endocrine Dysregulation .............................................................................. 34 3.6 Learning and Memory ...................................................................................................... 36 3.7 Schizophrenia .................................................................................................................... 45 3.8 Epilepsy .............................................................................................................................. 48 3.9 Pain ..................................................................................................................................... 50 3.10 Migraine ........................................................................................................................... 56 3.11 Substance Abuse ............................................................................................................. 57 3.12 Locomotion ..................................................................................................................... 59 3.13 Respiratory System......................................................................................................... 61 3.14 Cardiovascular System .................................................................................................. 62 3.15 Micturition (Urination) .................................................................................................. 63 3.16 Mammary Gland ............................................................................................................. 64 3.17 Cancer and Fibrosis ........................................................................................................ 65 CHAPTER 4 5-HT7 RECEPTORS AND INFLAMMATORY BOWEL DISEASE .......................... 68 4.1 A Brief Introduction on Inflammatory Bowel Disease ................................................ 68 4.2 Serotonergic System and Intestinal Inflammation ....................................................... 70 4.3 The 5-HT7 Receptor Subtype as a Potential Target for IBD ....................................... 74 v CHAPTER 5 PRELIMINARY RESULTS ................................................................................................... 79 CHAPTER 6 SPECIFIC AIMS AND RESEARCH PLAN ...................................................................... 85 6.1 Specific Aims and Hypothesis ........................................................................................ 85 6.2 Specific Aim 1: Develop Butyrolactone Series and Generate SAR .......................... 86 6.2.1 Sub-Aim 1: Synthesize New Analogs and Develop Enantiomerically Pure Synthesis ........................................................................................................................ 86 6.2.1.1 Extend Preliminary Series ...................................................................................... 86 6.2.1.2 Explore Alternate Arylamine Systems ................................................................... 90 6.2.1.3 Piperazine Bioisosteres .......................................................................................... 92 6.2.1.3 Increasing Polarity of Lactone Appendage ............................................................ 95 6.2.1.4 Chiral Synthesis ....................................................................................................
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