고려대학교

목차

ABSTRACT i
국문 초록 iii
Table of Contents v
List of Table vii
List of Figures viii
List of Scheme ix
I. Introduction 1
1. Tauopathies and Tau protein 1
2. Tau and TDP-43 mixed pathology 4
3. Tau and TDP-43 Oligomers: A Therapeutic approach 6
II. Results and Discussion 8
1. Discovery of Protein Aggregation Inhibitors 8
1.1. Strategies for lead optimization 8
2. Chemistry: Synthesis of fused ring core derivatives 11
2.1. Development of Benzothiazole core derivatives 13
2.1.1. Biological evaluation of Benzothiazole core derivatives 14
2.2. Development of Benzoxazole core derivatives 18
2.2.1. Biological evaluation of pyridine and its substituted derivatives 19
2.2.2. Biological evaluation of cyclic amine and its substituted derivatives 24
2.2.3. Biological evaluation of morpholine, piperazine, and its substituted derivatives 27
2.3. Development of Benzimidazole core derivatives 30
2.3.1. Biological evaluation of Benzimidazole core derivatives 31
2.4. Development of fused pyridine ring core derivatives 34
2.4.1. Biological evaluation of fused pyridine core derivatives 37
3. Chemistry: Modification of Carbonohydrazonoyl dicyanide 38
3.1. Development of Benzoxazole, Benzimidazole derivatives 38
3.1.1. Biological evaluation of Carbonohydrazonoyl dicyanide modification compounds 42
4. Identification of 3R/4R Tau selective compounds 46
4.1. Biological evaluation 46
4.1.1. Evaluation of selectivity for tau isoforms via Tau-BiFC assay 46
4.1.2. Toxicity test and Pharmacokinetics study 48
4.1.3. In vivo analysis using TauP301L-BiFC mouse model 51
4.1.4. Behavior test: Novel Object Recognition (NOR) test, Y maze test, Balance beam test, Barnes maze test 56
III. Conclusions 60
IV. Discussion 63
V. Experimental section 64
1. General methods for synthesis 64
2. General methods for biological evaluation 64
3. Synthesis 66
References 175
Appendices 179