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Part I: Structure-activity relationship of human glutaminyl cyclase inhibitors having an N-(5-methyl-1H-imidazol-1-yl)propyl thiourea template. Part II: α-Substituted 2-(3-Fluoro-4-methylsulfonamidophenyl)acetamides as Potent TRPV1 Antagonists. : Part I: Glutaminyl cyclase 저해제로 N-(5-methyl-1H-imidazol-1-yl)propyl thiourea 골격계 화합물의 구조-활성 연구. Part II: 강력한 TRPV1 길항제로서 α-Substituted 2-(3-Fluoro-4-methylsulfonamidophenyl)acetamides 화합물의 연구.
DC Field | Value | Language |
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dc.contributor.advisor | 이지우 | - |
dc.contributor.author | 트란 프엉 타오 | - |
dc.date.accessioned | 2017-07-13T16:36:03Z | - |
dc.date.available | 2020-10-06T10:26:55Z | - |
dc.date.issued | 2015-08 | - |
dc.identifier.other | 000000053292 | - |
dc.identifier.uri | https://hdl.handle.net/10371/120098 | - |
dc.description | 학위논문 (박사)-- 서울대학교 대학원 : 약학과 약품화학전공, 2015. 8. 이지우. | - |
dc.description.abstract | PART II: α-Substituted 2-(3-Fluoro-4-methylsulfonamidophenyl)-acetamides as Potent TRPV1 Antagonists.
The transient receptor potential vanilloid 1 channel (TRPV1) has emerged as a very promising therapeutic target, reflecting its central role in nociception and its involvement in a range of diseases. Capsaicin and resiniferatoxin provided early structural leads for understanding the vanilloid pharmacophore, and it was soon recognized that appropriately modified derivatives were able to achieve antagonism. Of particular importance, hyperthermia represents a common side effect of TRPV1 antagonists and the pattern of antagonistic activities for different agonists has been suggested to be related to the ability of an antagonist to cause hyperthermia. Further, different antagonists are differentially affected by the signaling pathways that regulate TRPV1. The availability of novel antagonists will be critical for optimizing such characteristics. The structure of capsaicin (CAP) has been divided into three pharmacophoric regions. Correspondingly, the antagonistic template was subdivided into the same three pharmacophoric regions, namely the A-region (3-fluoro-4-methylsulfon amidophenyl), the B-region (propanamide), and the C-region ((6-trifluoromethyl-pyridin-3-yl)methyl). In order to gain better positioning of the C-region with the receptor through α-substitution in the B-region, with consequent enhancement of activity, we have extensively investigated the structure activity relationships of α-substituted acetamide derivatives for hTRPV1 antagonism. We describe incorporation of various alkyl, dialkyl and aryl groups at the α-position in the B-region, with 4-methylpiperidinyl and cyclohexylthio groups at the 2-position in the pyridine C-region, and we have evaluated their antagonism of CAP stimulation of hTRPV1 expressed in CHO cells. | - |
dc.description.tableofcontents | Table of Contents
Abstract i Table of Contents iv List of Tables viii List of Figures ix List of Schemes x I. PART I: STRUCTURE-ACTIVITY RELATIONSHIP OF HUMAN GLUTAMINYL CYCLASE INHIBITORS HAVING AN N-(METHYL-1H-IMIDAZOL-1-YL)PROPYL THIOUREA TEMPLATE. - 1 - 1. Introduction - 1 - 1.1. Alzheimers disease (AD) - 1 - 1.1.1. What is AD? - 1 - 1.1.2. What causes AD? - 2 - 1.1.3. Treatment of AD - 4 - 1.2. Glutaminyl Cyclase (QC) (EC 2.5.2.3) - 7 - 1.2.1. Overview of QC - 7 - 1.2.2. Role of QC - 9 - 2. Result and Dicussion - 10 - 2.1. Design - 10 - 2.2. Chemistry - 11 - 2.3. Biological Activity - 15 - 3. Conclusion - 19 - 4. Experiment section - 20 - 4.1. General Experimental - 20 - 4.2. Syntheses of Human glutaminyl cyclase inhibitors having an N-(5-methyl-1H-imidazol-1-yl)propyl thiourea template - 21 - 4.2.1. General procedure for thiourea coupling - 21 - 4.2.2. General procedure for reduction of the nitro group to the amine - 21 - 4.2.3. General procedure for Boc-protection - 21 - 4.2.4. General procedure for Boc-deprotection - 22 - 4.2.5. General procedure for N-methylation - 22 - 5. References - 50 - PART II: Α-SUBSTITUTED 2-(3-FLUORO-4-METHYLDULFONAMIDOPHENYL)-ACETAMIDES AS POTENT TRPV1 ANTAGONISTS. - 55 - 1. Introduction - 55 - 1.1. Overview about Pain - 55 - 1.1.1. What is Pain? - 55 - 1.1.2. Treatment of Pain - 57 - 1.2. TRPV1 Receptor - 61 - 1.2.1. Structure and Mechanism - 61 - 1.2.2. TRPV1 Agonists - 65 - 1.2.3. TRPV1 antagonists - 65 - 1.2.4. Structure Activity Relationship - 66 - 1.2.5. Recent Developments - 68 - 2. Result and Dicussion - 72 - 2.1. Design - 72 - 2.2. Chemistry - 74 - 2.3. Biological Activity - 78 - 3. Conclusion - 83 - 4. Expriment section - 83 - 4.1. General Experimental - 83 - 4.2. Biological experiment - 84 - 4.2.1. Functional Investigations on TRPV1 - 84 - 4.2.2. Method FLIPR-Capsaicin-Assay - 84 - 4.2.3. Method FLIPR-TRPV1-pH-Assay - 86 - 4.2.5. Method NADA-Assay TRPV1 - 88 - 4.2.6. Molecular Modeling - 90 - 4.3. Synthesis of the A/B-region for 109 (Scheme 14) - 91 - 4.4. Synthesis of the A/B-region for 110-131 (Scheme 15) - 93 - 4.4.1. General instructions for the synthesis of 2-cycloalkyl-2-(3-fluoro-4-(methylsulfonamido)phenyl)acetic acids - 93 - 4.4.2. Synthesis of 2-(3-fluoro-4-(methylsulfonamido)phenyl)-2-phenylacetic acid (100c) - 96 - 4.4.3. Synthesis of (3-fluoro-4-methanesulfonylamino-phenyl)-(3-fluoro-phenyl)-acetic acid (100d) - 99 - 4.4.4. Synthesis of (3-fluoro-4-methanesulfonylamino-phenyl)-o-tolyl-acetic acid (100f) - 102 - 4.4.5. Synthesis of (3-fluoro-4-methanesulfonylamino-phenyl)-m-tolyl-acetic acid (100g) - 107 - 4.4.6. Synthesis of 2-(3-fluoro-4-methanesulfonylamino-phenyl)-3-phenyl-propionic acid (100i) - 111 - 4.5. Synthesis of the A/B-region for 132-135 (Scheme 16) - 115 - 4.6. Synthesis of the A/B-region for 136-137 (Scheme 17) - 117 - 4.7. Synthesis of C-region amines (Scheme 18) - 120 - 4.8. General procedure for amide coupling (Scheme 19) - 121 - 5. References - 121 - | - |
dc.format | application/pdf | - |
dc.format.extent | 2286395 bytes | - |
dc.format.medium | application/pdf | - |
dc.language.iso | en | - |
dc.publisher | 서울대학교 대학원 | - |
dc.subject | Glutaminyl cyclase QC | - |
dc.subject | Alzheimer’s disease | - |
dc.subject | Enzyme inhibitor | - |
dc.subject | TRPV1 Antagonist | - |
dc.subject | Analgesis | - |
dc.subject | Capsaicin | - |
dc.subject | Molecular Modeling. | - |
dc.subject.ddc | 615 | - |
dc.title | Part I: Structure-activity relationship of human glutaminyl cyclase inhibitors having an N-(5-methyl-1H-imidazol-1-yl)propyl thiourea template. Part II: α-Substituted 2-(3-Fluoro-4-methylsulfonamidophenyl)acetamides as Potent TRPV1 Antagonists. | - |
dc.title.alternative | Part I: Glutaminyl cyclase 저해제로 N-(5-methyl-1H-imidazol-1-yl)propyl thiourea 골격계 화합물의 구조-활성 연구. Part II: 강력한 TRPV1 길항제로서 α-Substituted 2-(3-Fluoro-4-methylsulfonamidophenyl)acetamides 화합물의 연구. | - |
dc.type | Thesis | - |
dc.contributor.AlternativeAuthor | TRAN PHUONG THAO | - |
dc.description.degree | Doctor | - |
dc.citation.pages | 140 | - |
dc.contributor.affiliation | 약학대학 약학과 | - |
dc.date.awarded | 2015-08 | - |
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