Abstract
摘要:精神分裂症患者普遍會有四種症狀:正性症狀、負性症狀、情緒與認知相關症狀。世界上1%的成人患有精神分裂症,但是目前市場上的抗精神病藥物都是針對正性跟情緒相關症狀開發出來的藥,負性和認知相關症狀至今還沒有上市的藥,所以精神分裂症的負性症狀是一個急需被重視的未滿足的醫藥需求。根據精神分裂症負性症狀的潛在市場評估,其潛在市場預估近美金15 億(2022),全球精神分裂症市場預估從2012 年的美金63 億會成長到80 億(2022),再者一般患有精神疾病的病人都需要長期(每天)用藥,可預期市場非常的可觀。
我們開發新型N-methyl-D-aspartate receptor (NMDA)受體調節劑之D-amino acide oxidase (DAO) 抑制劑來舒緩精神分裂症病人的負性症狀。在臨床上羅氏臨床二期(270 以上個案)成功的Bitopertin 即是在此途徑上,故得知此途徑會改善負性症狀也能間接改善正性症狀,有一石二鳥的作用!另外,我們知道全世界的精神分裂症患者腦部D-胺基酸氧化酶表現量及活性會增加,D-胺基酸氧化酶抑制劑主要提高神經突觸間隙的D-serine 濃度,直接作用於神經突觸NMDA 受體,以提高NMDA 受體的鈣離子通透性,而活化NMDA 受體,改善精神分裂症的負性症狀。如前所示,作用於NMDA 傳遞路徑上的抑制劑已被證明能直接治療負性症狀,同時能改善正性症狀,如果有一個好的化合物能針對NMDA 途徑而被開發,這將對病人非常有所助益。
在本研究中,我們的研究團隊將持續D-胺基酸氧化酶抑制藥物的開發。我們已合成製造一系列的化合物(72 號系列),目前的先導藥物為72 號系列的衍生物267 號,在動物的藥效試驗部分,口服 5 mg/kg 對小鼠的社交互動 (social interaction) 負性症狀有明顯改善效果。此外,72 號化合物及衍生物皆已有美國暫時性專利。接續的兩年時間,我們將持續先導藥物的最佳化,研究包括:
1. 利用藥物結構定量構效關係最佳化267 新先導藥物包括以酵素IC50 量測以及細胞抑制活性評估。
2. 新的先導藥物合成、純度測試以及設計候選藥物的大量合成。
3. 體內藥效評估包括負性症狀動物實驗、社交互動,無法快樂(anhedonia)、絕望(forced swimming
test)、缺乏積極性(avolition)及認知功能測試 pre-pulse inhibition。
4. 藥物安全性測試包含中樞神經、心臟血管、呼吸及肝腎功能等安全性測試。
5. 藥物的吸收、分佈、代謝等藥物動力學分析。
這些實驗主要期待得到最佳的候選藥物,用以申請專利合作條約(PCT),並且使最終的候選藥物得以進入臨床試驗。
Abstract: It has been reported that schizophrenic patients have increased D-amino acid oxidase (DAO) genetic expression and enzymatic activity in their postmortem brain. The D-amino acid oxidase inhibitors (DAOI) are mainly elevating the D-serine level in the neuronal synaptic cleft and directly binding with the N-methyl-D-aspartate (NMDA) receptor. This binding may elevate the calcium ion influx and activate the NMDA receptor to improve the schizophrenia negative symptoms. Currently, there is no drugs or compounds in the pipeline for treating negative symptoms in schizophrenia patients while most anti-schizophrenia are focused on positive and mood symptoms in schizophrenia. The expected market estimated is 1.5 billions USD for negative symptoms in schizophrenia in 2022 and 8 billions USD for entire schizophrenia treatment. It has been demonstrated that inhibitors acting on NMDA pathway can directly treat negative symptoms and improve positive symptoms directly at the same time. It will be very beneficial to patients if a good compound is developed on the NMDA pathway.
In this study, our research team will continue our effort to develop DAO inhibitors to act on NMDA pathway for treating schizophrenia. We have identified, synthesized and created a series of compounds called drug No. 72 series. Our current lead is the derivative No. 267. In the in vivo animal efficacy study, oral 5 mg/kg of 267 improved the ketamine-induced social withdrawal negative symptom. We also have
obtained Drug No. 72 and its derivatives have obtained a provisional patent from the States. In this study, we will continue our effort in lead optimization with the following action items:
1. The quantitative structure-activity relationship (QSAR) guided lead optimization. We will start from our current lead, No. 267 lead with feedback from structure modifications, enzymatic and cell-based assays.
2. The chemical syntheses for more optimized structures. Also, large scale syntheses planning will be performed.
3. Compounds with good IC50 from enzymatic and cell based assay will proceed for in vivo efficacy animal studies. These animal experiments include the negative symptoms of social interaction, anhedonia, forced swimming tests, avolition measurements, and the cognitive functional test using prepulse inhibition (PPI).
4. Safety pharmacology assays will be performed to ensure little and no toxicities in the central nervous system (CNS), cardiovascular system, respiratory, liver, and kidney etc.
5. Drug absorption, distribution, metabolism and pharmacokinetics of DMPK analyses will also be performed and the data will also be included in the structure modeling process.
We expect to obtain a candidate for Patent Cooperation Treaty (PCT), and the investigational new drug for advancing the final candidate for clinical trials.
Keyword(s)
N-methyl-D-aspartic Acid (NMDA) 受體
D-胺基酸氧化酶
D-胺基酸氧化酶
抑制劑
臨床前試驗
72 號藥
N-methyl-D-aspartic Acid (NMDA) receptor
D-amino acid oxidase (DAO)
DAO inhibitor (DAOI)
preclinical trial
Di-amine compounds
Schizophrenia