集落刺激因子-1受體（CSF1R）是一種跨膜糖蛋白，表達於中樞神經系統小膠質細胞中，於細胞膜內具有激酶（kinase）結構，屬於III型受體酪氨酸激酶家族，同家族中還包括了c-KIT、FLT3和PDGFRα/β等激酶。越來越多的研究顯示以CSF1R作為靶點對於小膠質細胞的抑制，可以用來改善急性腦創傷、帕金森氏症、阿茲海默症等相關腦部退化性疾病之預後。現今文獻中已有許多藥效分子具有CSF1R抑制活性。然而，這些化合物大多僅對 III 型受體酪氨酸激酶家族顯示出些微的選擇性。特別是在 CSF1R 和c-KIT 之間，由於其激酶域之蛋白質結構高度相似，僅有少數激酶抑制劑可選擇性的標靶CSF1R，而過強的c-KIT抑制效應已知存在骨髓新生抑制和頭髮脫色現象等副作用。另一方面，為了治療腦部疾病，藥物必須穿過血腦屏障才能達到中樞神經，因此血腦屏障的穿透能力亦是發展此類藥物的重要考量。然而，現今唯一核可的CSF1R抑制藥物pexidartinib，對 CSF1R 和c-KIT不具有選擇性，並且文獻指出其血腦屏障穿透率不佳，顯示目前仍有開發新穎CSF1R抑制劑之需求。
　　於本研究中，我們以實驗室先前所發展的CSF1R的抑制劑做為基礎，根據CSF1R 和 c-KIT 結合袋口中關鍵的胺基酸差異，嘗試以位阻效應之方式來減少化合物對於 c-KIT 的活性。文獻指出胺基酸序列差異主要位於兩處，一個位於 DFG 區域，另一個則位於 αC-螺旋區域，而我們分別對於兩部分進行結構與活性關係之研究。值得一提的是，利用αC-螺旋區域內的差異來提升對於CSF1R選擇性的方式具有良好的效果，此方法於先前文獻中未被提及。另一方面，我們亦致力於找尋新穎的核心結構以開發不同類型的激酶抑制化合物，以改善原先喹唑啉化合物潛在的溶解度問題並預測改善藥物的血腦屏障穿透率。在此設計下，我們發現93 在 CSF1R 和 c-KIT 之間展現出最佳的選擇性（> 790 倍），而化合物90、92、127、143、147也能表現出比先導化合物BPR1R062、BPR1R149更好的選擇性。此外，BPR1R149表現出體內口服能力和腦滲透性等藥物動力學特性，與治療腦部疾病相關的臨床前研究正在進行中。

Colony-stimulating factor-1 receptor (CSF1R), a transmembrane glycoprotein majorly expressing on microglia in CNS, belongs to type III receptor tyrosine kinase family, which is also including FLT3, c-KIT, and PDGFRα/β. Recently, more and more studies have shown that the inhibition of microglia by targeting CSF1R can be used to improve the prognosis of traumatic brain injury, Parkinson's disease, Alzheimer's disease and other related neurodegenerative diseases. There are many pharmacodynamic molecules in the literature today with CSF1R inhibitory activity. However, most of these compounds show only slight selectivity for the type III receptor tyrosine kinase family, especially between CSF1R and c-KIT, due to the highly similar protein structure of their kinase domains. Only a few kinase inhibitors can selectively target CSF1R, since excessive c-KIT inhibitory is known to cause myelogenesis suppression, hair depigmentation and other side effects. On the other hand, in order to treat brain diseases, drugs must pass through the blood-brain barrier (BBB) to reach the central nervous system, so the penetration ability of the blood-brain barrier is also an important consideration for the development of such drugs. However, the only approved CSF1R inhibitory drug, pexidartinib, is not selective between CSF1R and c-KIT, and t its blood-brain barrier penetration ratio is not good, indicating that there is still a need for the development of novel CSF1R inhibitors.
In this study, based on the CSF1R inhibitors previously developed by our laboratory, we tried to reduce the c-KIT activity by the steric effects of compounds based on the key amino acid differences in the binding pockets of CSF1R and c-KIT. Several literature reports reveal that the amino acid sequence differences are mainly located in two places; one is located in the DFG region and the other is located in the αC-helix region. We will study the relationship between the structure activity relationship of the two parts respectively. It is worth mentioning that the use of differences within the αC-helix region to enhance the selectivity for CSF1R is a good approach, which has not been mentioned in the previous literatures. On the other hand, we are also continuing to search novel core structures to solve the current solubility problems of the original quinazoline compounds and improve the blood-brain barrier penetration rate of drugs. Under this design, we found that 93 exhibited the best selectivity (>790-fold) between CSF1R and c-KIT, while compounds 90, 92, 127, 143, 147 also exhibited better selectivity than the lead compound BPR1R062 and BPR1R149. In addition, BPR1R149 exhibits pharmacokinetic properties such as in vivo oral ability and brain permeability, and preclinical studies related to the treatment of brain diseases are ongoing.

壹、緒論...1
1.1 前言...1
1.2 癌症的治療...2
1.3 腦部疾病與治療方式...6
1.4 小膠質細胞 (Microglia)...9
1.4.1 小膠質細胞型態與運作方式...9
1.4.2 小膠質細胞的好與壞...11
1.5 蛋白質激酶 (Protein kinase)...12
1.5.1 激酶運作方式...12
1.5.2 激酶抑制劑...13
1.6 免疫激酶 (Immuno kinase)...18
1.7 癌症免疫治療 (Cancer immunotherapy)...25
1.8 集落刺激因子1受體 (Colony stimulating factor 1 receptor, CSF1R)...29
1.8.1 CSF1R 結構...31
1.8.2 CSF1R 活化過程...32
1.8.3 CSF1R 訊息傳遞路徑...33
1.9 與CSF1 / CSF1R 相關的疾病...35
1.9.1 CSF1R 與腫瘤的相關性...36
1.9.2 CSF1R 與神經性退化性疾病的關聯性...37
1.10 CSF1R 抑制劑與相關適應症...38
1.11 幹細胞生長因子受體 (Stem cell factor receptor, c-KIT)...49
1.11.1 c-KIT 結構...49
1.11.2 c-KIT 活化過程...50
1.11.3 c-KIT 訊息傳遞路徑...50
1.12 與c-KIT 相關的疾病...51
1.13 c-KIT 抑制劑...51
1.14 抑制c-KIT產生之不良現象...52
貳、研究動機...54
2.1 CSF1R抑制劑最佳化之開發歷程-具喹唑啉核心結構之BPR1R062...54
2.2 研究構想...56
2.2.1 先導化合物BPR1R062末端側鏈優化 (Terminal side chain optimization of lead compound BPR1R062)...58
2.2.2 末端側鏈的優化 (Terminal moiety variation)...58
2.2.3 增大連接體立障 (Increasing the steric hindrance of the linker)...62
2.2.4 骨架躍遷 (Scaffold hopping)...63
2.3 生物活性測試分析...64
2.3.1 酵素抑制活性測試 (Enzyme assay)...64
2.3.1.1 CSF1R抑制活性測試 (CSF1R enzyme assay)...64
2.3.1.2 c-KIT抑制活性測試 (c-KIT enzyme assay)...66
2.3.2 細胞株生長抑制測試 (Cell assay)...67
2.3.3 微粒體代謝穩定性測試 (Microsomal stability assay)...68
2.3.4 藥物動力學測試 (Pharmacokinetics study, PK)...69
參、結果與討論...70
3.1 不同末端胺類側鏈對於活性以及選擇性的影響...71
3.1.1 吲哚喹唑啉中間體合成...72
3.1.2 末端胺類側鏈合成...73
3.1.3 高轉換率之吲哚喹唑啉中間體合成...75
3.1.4 末端胺類側鏈衍生物合成...75
3.1.5 胺類側鏈化合物活性以及選擇性分析...77
3.1.6 胺類側鏈化合物穿腦數值預測...79
3.2 不同末端苯胺側鏈對於活性以及選擇性的影響...80
3.2.1 末端苯胺類側鏈合成...81
3.2.2 BPR1R149衍生物88-96之合成...87
3.2.3 苯胺側鏈系列化合物之活性與選擇性分析...88
3.2.4 苯胺側鏈化合物穿腦數值預測以及藥物動力學數值探討...92
3.3 1,5連接改成3,6連接吲哚連接體搭配不同末端側鏈對活性以及選擇性的影響...94
3.3.1 1,5連接改成3,6連接吲哚醯胺衍生物合成...95
3.3.2 1,5連接改成3,6連接吲哚系列化合物活性與選擇性分析...99
3.3.3 1,5連接改成3,6連接吲哚系列化合物穿腦數值以及藥物動力學數值探討...100
3.4 增加吲哚連接體立障對活性以及選擇性的影響...102
3.4.1 增加吲哚連接體立障衍生物之合成...103
3.4.2 增加吲哚連接體立障系列化合物之活性與選擇性分析...108
3.4.3 增加吲哚連接體立障系列化合物穿腦數值預測...112
3.5 骨架躍遷 (Scaffold hopping) 活性比較...112
3.5.1 BPR1R024 (39) 骨架躍遷衍生物之合成...114
3.5.2 BPR1R062 (40) 骨架躍遷衍生物之合成...117
3.5.3 骨架躍遷衍生物之活性分析與穿腦數值預測...125
3.6 吲哚系列衍生物光譜解析...130
肆、總結...135
4.1 先導化合物BPR1R062激酶選擇性最佳化與穿腦能力的提升...135
4.2 骨架躍遷-新穎核心結構之發現及穿腦潛力探討...140
4.3 未來展望...141
伍、實驗部分...143
5.1 一般實驗方法...143
5.2 化合物合成步驟與光譜資料...146
陸、參考資料...300
附錄一、化合物之核磁共振光譜圖...308
附錄二、化合物之編號對照表...387
附錄三、生物活性測試方法...390
附錄四、論文口試投影片...393

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