CN112773798A - 作为d-氨基酸氧化酶抑制剂的已知化合物的用途 - Google Patents
作为d-氨基酸氧化酶抑制剂的已知化合物的用途 Download PDFInfo
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Abstract
本发明涉及作为D‑氨基酸氧化酶抑制剂的已知化合物的用途。本发明利用虚拟筛选策略来寻找目前市场上的药物作为抗精神分裂症疗法，即药物再利用。药物再利用策略发现既有药物原本医学适应症以外的新用途。由于已知药物通常具有可接受的安全性及药物动力学特性，故发现这些药物的新的适应症将使有需要的患者更早的受益于潜在新疗法。在此研究中，利用对出售药物及其代谢物的虚拟筛选实施对用于DAAO抑制剂的出售药物作为新颖精神分裂症疗法的再利用。利用活体外DAAO酶抑制分析进一步证实经鉴别且可用的药物及化合物。
Description
本申请是申请日为2015年4月30日、申请号为201580021632.9、发明名称为“作为D-氨基酸氧化酶抑制剂的已知化合物的用途”的发明专利申请的分案申请。
技术领域
本发明涉及作为D-氨基酸氧化酶抑制剂的已知化合物的用途。本发明涉及D-氨基酸氧化酶(DAAO)抑制剂。具体而言，本发明涉及选择已知化合物作为DAAO抑制剂。
背景技术
已报导麸胺酸盐传递对N-甲基-D-天冬胺酸(NMDA)受体的异常调控机制为精神分裂症的神经病理学之一。所述受体是由NMDA受体1(NR1)及NR2的两个结构亚单位构成的异四聚体。所述两个亚单位的细胞外结构域负责调节及配体结合功能，其中NR1结合共激动剂甘胺酸，且NR2结合神经传递质麸胺酸盐。膜信道结构域负责钙离子的进入。所述受体需要结合NR2亚单位的麸胺酸盐以活化受体，且对于离子通道的高效开放其需要结合甘胺酸的共激动剂。调节NMDA受体的甘胺酸结合位点可改良精神分裂症中的认知功能及阴性症状。发现D-氨基酸氧化酶(DAAO)参与NMDA受体的活化过程。DAAO的受质、尤其D-丝胺酸可作为共激动剂结合至NMDA受体的甘胺酸位点。此又可在开放NMDA受体的钙通道中调控所述受体。已发现D-丝胺酸可抑制大鼠海马神经元中α-胺基-3-羟基-5-甲基-4-异恶唑丙酸(AMPA)受体介导的电流(Gong,X.Q.等人,Canadian Journal of Physiology andPharmacology 2007,85(5),546-55)。因此，假设DAAO与精神分裂症的发病机制相关。由于NMDA受体亦参与情感病症(Raster,M.P.等人,Pharmacological reports:PR 2012,64(3),706-13)，故抑制DAAO可提升NMDA的功能并改良精神分裂症的症状及抑郁情感病症(Hashimoto,K.等人,European Archives of Psychiatry and Clinical Neuroscience2013)。
精神分裂症是毁灭性的精神病症，其折磨约1％的世界人口。与此病症相关的直接及间接损失使得所述病症的费用极大(Abbott A.Nature,2010；468:158-9)。临床上，精神分裂症的特征主要在于阳性症状(包括妄想及幻觉)、阴性症状(例如情感迟钝、兴致缺乏及社会隔离)及认知缺陷(例如执行功能损害、注意力损害及工作记忆损害)。关于源于抗精神病药物治疗的精神分裂症病理生理学的初始且最常见的假设是多巴胺(dopamine)假设，尤其对于阳性症状的治疗而言(Howes,O.D；Kapur,S,Bulletin,2009,35(3),549-62；Madras,B.K,Journal of the History of the Neurosciences,2013,22(1),62-78)。与阳性症状相反，阴性症状及认知缺陷直至最近才获得相当大的关注。不幸地，可用的抗精神病药物对于改良阴性症状亦及认知缺陷相对无效。在首次发现抗精神病药物达半个多世纪之后，所述领域发现其本身不仅需要替代医药且亦需要替代靶标，尤其对于阴性及认知症状而言(Abbott A.Nature,2010；468:158-9)。
作为基于神经传递质的理论的起始点，N-甲基-D-天冬胺酸盐受体(NMDAR)介导的信号传导路径的功能不足与相关的学习、社交损害、长期增强及各种类型的学习及记忆累积相关(Riedel G,Platt B,Micheau Behavioural Brain Res.2003；140:1-47)。通过以下观察证实精神分裂症中NMDAR系统的涉及：NMDAR拮抗剂(亦即，苯环己派啶(phencyclidine，PCP)及氯胺酮(ketamine))诱导的类似于精神分裂症的阴性症状及认知功能障碍表明NMDAR可能尤其与精神分裂症的持久性差预后结果形式相关(Moghaddam B,Javitt D.Neuropsychopharmacology,2012；37:4-15)。但仍不清楚麸胺酸能功能障碍对精神分裂症的病因学的效应，积聚研究亦表明麸胺酸能神经传递的失调可参与精神分裂症的病理生理学(Goff DC,Coyle JT.Am J Psychiatry,2001；158:1367-77；MoghaddamB.Neuron,2003；40:881-4；Lin CH,Lane HY,Tsai GE.Pharmacol Biochem Behav,2012；100:665-77)。在NMDAR模型的最简单版本中，治疗的主要目标应为恢复NMDAR本身或除NMDAR外的其他靶标处的功能(Moghaddam B,Javitt D.Neuropsychopharmacology,2012；37:4-15)。因此，精神分裂症患者中麸胺酸能传递的功能不足是治疗的潜在靶标，且已认为增强NMDAR功能的药物为潜在疗法(Lin CH,Lane HY,Tsai GE.Pharmacol Biochem Behav,2012；100:665-77)。NMDAR是异聚复合物，其含有NR1、NR2及NR3亚单位。NMDAR亦含有麸胺酸盐识别位点(于NR2亚单位中)及甘胺酸调节位点(于NR1亚单位中)。麸胺酸盐及甘胺酸皆是NMDAR的激动剂(Clements JD,Westbrook GL.Activation kinetics reveal the numberof glutamate and glycine binding sites on the N-methyl-d-aspartatereceptor.Neuron,1991；7:605-613)。由于对NMDAR的麸胺酸盐结合位点的直接刺激可产生兴奋毒性神经元死亡，故通过靶向NMDAR的甘胺酸位点或D-丝胺酸位点来增强NMDAR功能可能较有益。一个有前景的靶标是D-氨基酸氧化酶(DAO,DAAO)，所述酶是代谢D-丝胺酸(内源性NMDAR的共激动剂)的黄素酶。因此，其可调节NMDAR功能且可有助于精神分裂症中广泛假设的NMDAR信号传导涉及。同样，来自三种证据的积聚资料支持此可能性(L Verrall,PWJBurnet,JF Betts及PJ Harrison,Mol Psychiatry.2010年2月；15(2):122-137)。(1)在若干而非所有研究中，DAO显示与病症具有遗传相关性；(2)在精神分裂症中，DAO的表达及活性有所增加；及(3)在啮齿动物中，DAO的失活引起行为及生物化学效应，表明潜在治疗益处。由于认为NMDAR功能障碍参与精神分裂症的阳性、阴性及认知症状，故人们对研发对于治疗精神分裂症的阴性及认知症状有效且具选择性的DAO抑制剂极为感兴趣(SeanMSmith,Jason M Uslaner及Peter HHutson,Open Med Chem J.2010；4:3-9)。
已报导NMDA受体增强剂具有以下适应症：(i)治疗精神分裂症及情感性精神分裂症的所有症状范围，包括阴性、认知、抑郁、阳性及一般精神病理学症状范围(Tsai,G.E.及P.Y.Lin,Curr Pharm Des,2010.16(5):第522-37页；及Singh,S.P.及V.Singh,CNS Drugs,2011.25(10):第859-85页)；(ii)治疗抑郁(Huang,C.C.,等人,Biol Psychiatry,2013.74(10):第734-41页)；(iii)治疗帕金森氏病(Parkinson's disease)(Gelfin,E.,等人,IntJ Neuropsychopharmacol,2012.15(4):第543-9页；(iv)治疗妥瑞氏症候群(TouretteSyndrome)(Singer,H.S.,C.Morris及M.Grados,Med Hypotheses,2010.74(5):第862-7页)；(v)治疗轻度认知损害(MCI)及阿兹海默病(Alzheimer disease，AD)(Lin,C.H.,等人,Biol Psychiatry,2014.75(9):第678-85页)；(vi)治疗创伤后压力病症(PTSD)(Heresco-Levy,U.等人,Int J Neuropsychopharmacol,2009.12(9):第1275-82页；Difede,J.等人,Neuropsychopharmacology,2014.39(5):第1052-8页)；(vii)治疗强迫行为病症(OCD)(Wu,P.L.等人,J Clin Psychopharmacol,2011.31(3):第369-74页；及Wilhelm,S.等人,Am JPsychiatry,2008.165(3):第335-41页；quiz409)；(viii)痛觉缺失(Gong,N.等人,Neuropharmacology,2012.63(3):第460-8页)。
D-丝胺酸是NMDA受体的变构甘胺酸结合位点处的完全激动剂，且据报导可改良精神分裂症(Ferraris,D.V.等人,Current pharmaceutical design 2011,17(2),103-11)及抑郁(Hashimoto,K.等人,European Archives of Psychiatry and ClinicalNeuroscience 2013)中的阴性、认知症状及标准D2拮抗剂未能充分解决的症状。抑制DAAO可直接增加大脑D-丝胺酸含量，因此可潜在地用于精神分裂症疗法(Miyamoto,S.等人,Molecular psychiatry 2012,17(12),1206-27；Sacchi,S.等人,Current pharmaceuticaldesign 2012；Ono,K.等人,Journal of neural transmission(Vienna,Austria:1996)2009,116(10),1335-47)及甚至进一步情感病症。
已知的DAAO抑制剂包括苯甲酸、吡咯-2-甲酸及吲哚-2-甲酸。文献中已阐述用于治疗神经变性疾病及神经毒性损伤的吲哚衍生物且具体而言某些吲哚-2-甲酸酯。EP396124揭示用于治疗或管控由CNS病症或创伤事件引起的神经毒性损伤或者治疗或管控神经变性疾病的吲哚-2-甲酸酯及衍生物。美国专利第5,373,018号、第5,374,649号、第5,686,461号、第5,962,496号及第6,100,289号揭示使用吲哚衍生物治疗神经毒性损伤及神经变性疾病。WO 03/039540揭示DAAO抑制剂(包括吲哚-2-甲酸)及增强学习、记忆及认知的方法，以及治疗神经变性病症的方法。专利申请案第WO/2005/089753号揭示苯并异恶唑类似物及治疗精神病症(例如精神分裂症)的方法。最近，已报导诸如AS057278(5-甲基吡唑-3-甲酸)(Adage,T.等人,Eur Neuropsychopharmacol 2008,18(3),200-14)、CBIO(6-氯苯并[d]异恶唑-3-醇)(Ferraris,D.等人,J Med Chem 2008,51(12),3357-9)及来自Merck的4H-噻吩并[3,2-b]吡咯-5-甲酸(Smith,S.M.等人,J Pharmacol Exp Ther 2009,328(3),921-30)等化合物具有DAAO抑制效应。
业内需要研发具有DAAO抑制效应的候选药物以治疗各种神经及身体病症。
发明内容
本申请涉及一种化合物的用途，该化合物用于制备治疗及/或预防个体中与DAAO抑制相关的疾病的药剂。该化合物选自埃索美拉唑(esomeprazole)或其治疗上可接受的盐、前药或异构物。上述的由DAAO抑制介导的所述疾病是精神分裂症及情感性精神分裂症的症状范围、轻度认知损害、阿兹海默病、帕金森氏病、抑郁、妥瑞氏症候群、疼痛、运动失调、抽搐、创伤后压力病症(PTSD)、强迫行为病症(OCD)、精神分裂症、痛觉缺失、失智、与神经变性疾病相关的记忆及/或认知丧失或特征在于神经变性疾病的神经元功能丧失。
附图说明
图1显示5-O-去甲基-奥美拉唑(5-O-Desmethyl-Omeprazole)的结构分析。(a)与3-羟基喹啉-2(1H)-酮结合模式的比较。(b)结合有DAAO-FAD复合物的5-O-去甲基-奥美拉唑(c)5-O-去甲基-奥美拉唑的2D结构(d)用于结合5-O-去甲基-奥美拉唑的残基。绿色卡通图(carton)显示DAAO结构。粉色、蓝色及黄色棒分别展示FAD、3-羟基喹啉-2(1H)-酮及5-O-去甲基-奥美拉唑。紫色线是与5-O-去甲基-奥美拉唑相互作用的残基。黄色虚线是氢键结相互作用。
图2显示所选药物的IC50。
图3显示注射RS-D7可增加小鼠的伤害感受功能(A及B)及感觉运动门控功能(C)。
图4显示注射RS-D7可减轻注射有甲基安非他命(methamphetamine)(3mg/kg)的ICR小鼠的感觉运动门控缺陷。
图5显示在(A)蔗糖偏好性测试、(B及C)热板测试及(D)前脉冲抑制中在小鼠中注射RS-D7可减轻MK-801(0.2mg/kg)诱导的行为缺陷。
具体实施方式
本发明是基于发现已知药物及化合物作为潜在DAAO抑制剂(即药物再利用)的主意，利用药物数据库实施基于结构的虚拟筛选。本发明利用虚拟筛选策略来寻求目前市场的药物作为抗精神分裂症疗法，即药物再利用。药物再利用策略发现既有药物原本医学适应症以外的新用途。由于已知药物通常具有可接受的安全性及药物动力学特性，故发现这些药物的新的适应症将使有需要的患者更早的受益于潜在新疗法。在吾人的工作中，应用再利用策略从而发现DAAO抑制剂作为新的精神分裂症疗法，此是针对出售药物及其代谢物利用虚拟筛选来实施。利用活体外DAAO酶抑制分析进一步证实经鉴别且可用的药物及化合物。
除非另有说明，否则此申请案中所使用的所有科学及技术术语皆具有业内通常使用的含义。如此申请案中所使用，以下词语或词组具有所指定的含义。
术语「一(a及an)」是指一个或一个以上(亦即，至少一个)的所述冠词的文法受词。
除非明确指示仅指替代或除非替代互相排斥，否则术语「或」是指「及/或」。
术语「个体」包括活的有机体，例如人类、猴、母牛、绵羊、马、猪、牛、山羊、狗、猫、小鼠、大鼠、培养细胞及其转基因物种。在优选实施例中，个体是人。
术语「投与」包括容许本发明活性成分实施其预期功能的投与途径。
术语「治疗(treat或treatment)」是指降低疾病或病况的效应的方法。治疗亦可指降低疾病或病况本身的根本病因而非仅症状的方法。治疗可为自原来含量的任何降低且可为(但不限于)疾病、病况或疾病或病况的症状的完全消除。
术语「预防(prevent、prevention或preventing)」意指与靶标疾病相关的症状的抑制或防止。
词组「治疗有效量」是指以适用于任一医学治疗的合理益处/风险比有效产生期望治疗效应的化合物、材料或包含本发明化合物的组合物的量。
术语「神经病症」是指哺乳动物的中枢或周边神经系统的任一不希望有的病况。术语「神经病症」包括神经变性疾病(例如，阿兹海默病、帕金森氏病及肌肉萎缩性脊髓侧索硬化)、神经精神病学疾病(例如精神分裂症及焦虑，例如一般性焦虑病症)。例示性神经病症包括MLS(小脑性运动失调)、亨廷顿氏病(Huntington's disease)、唐氏症候群(Downsyndrome)、多发性梗塞失智、癫痫状态、挫伤性损伤(例如脊髓损伤及头部损伤)、病毒感染诱导的神经变性(例如AIDS、脑病变)、癫痫、良性健忘、闭合性颅脑损伤、睡眠病症、抑郁(例如，双极性病症)、失智、运动病症、精神病、酒精中毒、创伤后压力病症及诸如此类。「神经病症」亦包括与所述病症相关的任一不希望有的病况。例如，治疗神经变性病症的方法包括治疗与神经变性病症相关的记忆及/或认知丧失丧失的方法。所述方法亦可包括治疗或预防特征在于神经变性病症的神经元功能丧失。
在一个态样中，本发明提供治疗及/或预防个体的与DAAO抑制相关的疾病的方法，其包含向个体投与有效量的化合物选自由以下组成的群：埃索美拉唑(esomeprazole)、奥氮平(olanzapine)、5-O-去甲基-奥美拉唑、(-)-反式4-(4-氟苯基)-3-(3-羟基-4-甲氧基苯氧基甲基)六氢吡啶(BRL 36583A)、(-)反式4-(4-氟苯基)-3-(4-羟基-3-甲氧基苯氧基甲基)六氢吡啶-盐酸盐(BRL 36610A)、胺酚喹(amodiaquin)、度洛西汀(duloxetine)、纳布啡(nalbuphine)及N-去甲基氯氮平(N-desmethylclozapine)或其治疗上可接受的盐、溶剂合物、前药或异构物。
在其他态样中，本发明提供抑制个体中麸胺酸盐传递对N-甲基-D-天冬胺酸(NMDA)受体的异常调控机制的方法，其包含向个体投与有效量的选自由以下组成的群的化合物：埃索美拉唑、奥氮平、5-O-去甲基-奥美拉唑、(-)-反式4-(4-氟苯基)-3-(3-羟基-4-甲氧基苯氧基甲基)六氢吡啶(BRL 36583A)、(-)反式4-(4-氟苯基)-3-(4-羟基-3-甲氧基苯氧基甲基)六氢吡啶-盐酸盐(BRL 36610A)、胺酚喹、度洛西汀、纳布啡及N-去甲基氯氮平或其治疗上可接受的盐、溶剂合物、前药或异构物。因此，本发明提供选自由以下组成的群的化合物的用途：埃索美拉唑、奥氮平、5-O-去甲基-奥美拉唑、(-)-反式4-(4-氟苯基)-3-(3-羟基-4-甲氧基苯氧基甲基)六氢吡啶(BRL 36583A)、(-)反式4-(4-氟苯基)-3-(4-羟基-3-甲氧基苯氧基甲基)六氢吡啶-盐酸盐(BRL 36610A)、胺酚喹、度洛西汀、纳布啡及N-去甲基氯氮平或其治疗上可接受的盐、溶剂合物、前药或异构物，其用于制造用以抑制个体中麸胺酸盐传递对N-甲基-D-天冬胺酸(NMDA)受体的异常调控机制的医药。
在其他态样中，本发明提供抑制个体中N-甲基-D-天冬胺酸盐受体(NMDAR)介导的信号传导路径的功能不足的方法，其包含向个体投与有效量的选自由以下组成的群的化合物：埃索美拉唑、奥氮平、5-O-去甲基-奥美拉唑、(-)-反式4-(4-氟苯基)-3-(3-羟基-4-甲氧基苯氧基甲基)六氢吡啶(BRL 36583A)、(-)反式4-(4-氟苯基)-3-(4-羟基-3-甲氧基苯氧基甲基)六氢吡啶-盐酸盐(BRL36610A)、胺酚喹、度洛西汀、纳布啡及N-去甲基氯氮平或其治疗上可接受的盐、溶剂合物、前药或异构物。因此，本发明提供选自由以下组成的群的化合物的用途：埃索美拉唑、奥氮平、5-O-去甲基-奥美拉唑、(-)-反式4-(4-氟苯基)-3-(3-羟基-4-甲氧基苯氧基甲基)六氢吡啶(BRL 36583A)、(-)反式4-(4-氟苯基)-3-(4-羟基-3-甲氧基苯氧基甲基)六氢吡啶-盐酸盐(BRL 36610A)、胺酚喹、度洛西汀、纳布啡及N-去甲基氯氮平或其治疗上可接受的盐、溶剂合物、前药或异构物，其用于制造用以抑制个体中N-甲基-D-天冬胺酸盐受体(NMDAR)介导的信号传导路径的功能不足的医药。
下文列示上文所提及化合物的结构：
本发明化合物可用于治疗或预防任何疾病及/或病况，其中调节D-丝胺酸含量及/或其氧化产物可有效改善症状。抑制酶可使得增加D-丝胺酸含量及减少毒性D-丝胺酸氧化产物的形成。因此，本发明提供治疗或预防神经病症的方法及增强学习、记忆及/或认知的方法。本发明亦提供治疗或预防以下的方法：由DAAO抑制介导的疾病；优选地，精神分裂症及情感性精神分裂症的症状范围、抑郁、妥瑞氏症候群、创伤后压力病症(PTSD)、强迫行为病症(OCD)、痛觉缺失、与神经变性疾病相关的记忆及/或认知丧失，或特征在于神经变性疾病的神经元功能丧失。在一些实施例中，精神分裂症及情感性精神分裂症的症状范围包括阴性、认知、抑郁、阳性及一般精神病理学症状范围。在另一实施例中，与DAAO抑制相关的疾病是轻度认知损害(MCI)、阿兹海默病、帕金森氏病或精神分裂症。在一些实施例中，与DAAO抑制相关的疾病是疼痛、运动失调或抽搐。在一些实施例中，本发明化合物可用于治疗或预防与神经变性疾病相关的记忆及/或认知丧失(例如，阿兹海默病及精神分裂症)并预防特征在于神经变性疾病的神经元功能丧失。另外，提供治疗或预防疼痛、运动失调及抽搐的方法。
在一些实施例中，本文所阐述化合物的有效量在2mg/kg体重至5g/kg体重的范围内；优选地，10mg/kg体重至3g/kg体重或20mg/kg体重至2g/kg体重。
医药上可接受的载剂、稀释剂、赋形剂及/或盐意指载剂、稀释剂、赋形剂及/或盐必须与活性成分兼容，不会不利地影响活性成分的治疗益处，且对其接受者无害。
可通过全身及/或局部(例如，在骨折、截骨术或矫形外科手术的位点)递送化合物的任一方法投与活性成分或其医药组合物从而实践本发明。这些方法包括经口途径、非经肠途径、十二指肠内途径等。
对于局部施加，可将活性成分或其医药组合物调配成含有悬浮或溶解于一或多种载剂中的活性组份的适宜软膏。用于局部投与活性成分或其医药组合物的载剂包括(但不限于)：矿物油、液体石蜡脂、白石蜡脂、丙二醇、聚氧乙烯、聚氧丙烯化合物、乳化蜡、糖(例如乳糖)及水。另一选择为，可将医药组合物调配成含有悬浮或溶解于一或多种医药上可接受的载剂中的活性组份或其医药组合物的适宜洗剂或乳霜中。适宜载剂包括(但不限于)矿物油、山梨醇酐单硬脂酸酯、聚山梨醇酯60、十六烷基酯蜡、鲸蜡醇、2-辛基十二烷醇、苯甲醇及水。
端视欲治疗的病况、病症或疾病而定，可连同活性成分或其医药组合物一起投与其他治疗剂。彼等其他药剂可作为多剂量方案的一部分以任一顺序依序自活性成分或其医药组合物投与(连续或间歇投与)。另一选择为，彼等药剂可为单一剂型的一部分，与活性成分或其医药组合物混合在一起(同时或并行投与)。
对于经口投与，可用于本发明中的医药组合物可采取以下形式：溶液、悬浮液、锭剂、丸剂、胶囊、粉末、颗粒、半固体、持续释放型调配物、酏剂、气溶胶及诸如此类。含有各种赋形剂(例如柠檬酸钠、碳酸钙及磷酸钙)的锭剂可连同各种崩解剂(例如淀粉(优选地马铃薯或树薯淀粉)及某些复杂硅酸盐)一起、连同结合剂(例如聚乙烯吡咯啶酮、蔗糖、明胶及阿拉伯胶)一起使用。另外，润滑剂(例如硬脂酸镁、月桂基硫酸钠及滑石粉)通常极可用于压锭目的。亦采用相似类型的固体组合物作为软填充及硬填充明胶胶囊中的填充剂；就此而言，优选材料亦包括乳糖或牛乳糖以及高分子量聚乙二醇。当期望经口投与水性悬浮液及/或酏剂时，可将本发明的活性成分或其医药组合物与各种甜味剂、矫味剂、着色剂、乳化剂及/或悬浮剂以及稀释剂(例如水、乙醇、丙二醇、甘油及其各种组合)组合。
本文所用术语「非经肠」是指包括静脉内、肌肉内、腹膜腔内、胸骨内、皮下、脊髓内及关节内注射及输注的投与模式。非经肠注射的医药组合物可包含医药上可接受的无菌水性或非水性溶液、分散液、悬浮液或乳液以及在即将使用前重构成为无菌可注射溶液或分散液的无菌粉末。水性溶液尤其适于静脉内、肌内、皮下及腹膜腔内注射目的。就此而言，所用无菌水性介质皆易于通过熟习此项技术者众所周知的标准技术获得。适宜水性及非水性载剂、稀释剂、溶剂或媒剂的实例包括水、乙醇、多元醇(例如甘油、丙二醇、聚乙二醇及诸如此类)、羧甲基纤维素及其适宜混合物、植物油(例如橄榄油)及可注射的有机酯(例如油酸乙酯)。例如，可通过使用诸如卵磷脂等包覆材料、通过维持所需粒径(在分散液情况下)且通过使用表面活性剂来维持适当流动性。
可用于本发明中的医药组合物亦可含有佐剂，例如(但不限于)防腐剂、润湿剂、乳化剂及分散剂。微生物作用的预防可通过纳入各种抗细菌及抗真菌剂来确保，例如，对羟基苯甲酸酯、氯丁醇、苯酚山梨酸及诸如此类。亦可合意地包括等渗剂，例如糖、氯化钠及诸如此类。可通过纳入延迟吸收的药剂(例如单硬脂酸铝及明胶)达成可注射医药形式的延长吸收。
当使用鞘内或硬膜外途径时，具体而言可用通过缓慢输注的投与。业内已知可用于以受控速率递送化合物的可植入或可安装在身体上的帮浦的数量。例如参见美国专利第4,619,652号。
除活性化合物外，悬浮液亦可含有悬浮剂，例如乙氧基化异硬脂醇、聚氧乙烯山梨醇及山梨醇酐酯、微晶纤维素、偏氢氧化铝、膨润土、琼脂及黄蓍胶及其混合物。
出于经皮(例如，局部)投与的目的，制备在其他方面类似于上述非经肠溶液的稀的无菌水性或部分地水性溶液(浓度通常为约0.1％至5％)。
可用于本发明中的医药组合物亦可通过鼻气溶胶或吸入投与。这些组合物可根据医药调配领域熟知的技术来制备且可制备为盐水溶液，其采用苯甲醇或其他适宜防腐剂、吸收促进剂(用于增强生物可用性)、氟碳化合物及/或其他习用增溶剂或分散剂。
用于经直肠或经阴道投与的组合物优选为栓剂，其可通过将活性成分或其医药组合物与适宜无刺激性赋形剂或载剂(例如可可脂、聚乙二醇或栓剂蜡)混合来制备，这些赋形剂或载剂在室温下为固体但在体温下为液体，且因此可在直肠或阴道腔内融化并释放药物。
其他医药上可接受的载剂包括(但不限于)无毒固体、半固体或液体填充剂、稀释剂、囊封材料或任一类型的调配助剂，包括(但不限于)离子交换剂、氧化铝、硬脂酸铝、卵磷脂、血清蛋白(例如人类血清白蛋白)、缓冲物质(例如磷酸盐)、甘胺酸、山梨酸、山梨酸钾、饱和植物脂肪酸的偏甘油酯混合物、水、盐或电解质(例如硫酸鱼精蛋白、磷酸氢二钠、磷酸氢钾、氯化钠、锌盐、胶质二氧化硅、三硅酸镁、聚乙烯基吡咯啶酮、基于纤维素的物质、聚乙二醇、羧甲基纤维素钠、聚丙烯酸酯、蜡、聚乙烯-聚氧丙烯-嵌段共聚物、聚乙二醇及羊毛脂。
固体医药赋形剂包括(但不限于)淀粉、纤维素、滑石粉、葡萄糖、乳糖、蔗糖、明胶、麦芽、稻、面粉、白垩、硅胶、硬脂酸镁、硬脂酸钠、甘油单硬脂酸酯、氯化钠、脱脂乳粉及诸如此类。液体及半固体赋形剂可选自甘油、丙二醇、水、乙醇及各种油，包括石油、动物油、植物油或合成来源的油，例如，花生油、大豆油、矿物油、芝麻油等。优选液体载剂、尤其可注射溶液包括水、盐水、右旋糖水溶液及二醇。
熟习此项技术者已知或根据本发明将明了制备具有某一量的活性成分的各种医药组合物的方法。其他适宜医药赋形剂及其调配物阐述于Remington's PharmaceuticalSciences,E.W.Martin编辑,Mack Publishing Company,第19版,1995年中。
在其他态样中，本发明提供选择DAAO抑制剂的方法，其包含选择药物数据库；去除含有金属原子的化合物及分子量在100g/mol至700g/mol范围外的化合物；选择与DAAO的Leu51、Gln53、Leu215、His217、Tyr 224、Tyr228、Ile230、Arg283及Gly313中的三个以上残基相互作用的化合物候选者，及使所选化合物候选者经受抑制活性分析。
本发明方法中可使用任何药物数据库。通过去除含有金属原子的分子及分子量在100g/mol至700g/mol范围外的分子将化合物缩减成子组。为评价所选化合物在DAAO的活性位点中的可能的结合模式及相互作用型式，对这些化合物实施MSD。根据MDS的结果，分析在DAAO附近靠近每一化合物的残基。根据文献，DAAO的活性位点含有以下残基：Leu51、Gln53、Leu215、His217、Tyr 224、Tyr228、Ile230、Arg283及Gly313。将附近在
距离内具有三个以上上文所提及残基的分子视为候选者。通过实施本发明的选择方法获得本文所提及的DAAO抑制性化合物。
实例
实例1 DAAO抑制剂材料的选择
D-丙胺酸、3-(4-羟基苯基)丙酸(HPPA)、猪肾DAAO、过氧化物酶、Tris-base、埃索美拉唑、N-去甲基氯氮平、纳布啡及胺酚喹购自Sigma-Aldrich公司LLC.(Sigma-Aldrich,USA)。Tris-HCl盐购自invitrogen(Life Technologies公司,USA)。5-O-去甲基-奥美拉唑及奥氮平购自Toronto Research Chemicals(Canada)。PM-BRL 36583A及PM-BRL 36610A来自GlaxoSmithKline(United Kingdom)。度洛西汀购自Sequoia Research Products(United Kingdom)。黑色96孔板购自Nunc(Thermo Scientific,USA)。
虚拟筛选
自蛋白质数据库获得DAAO晶体结构(Schnell,E.；Sizemore,M.；Karimzadegan,S.；Chen,L.；Bredt,D.S.；Nicoll,R.A.,Direct interactions between PSD-95andstargazin control synaptic AMPA receptor number.Proc Natl Acad Sci US A 2002,99(21),13902-7)(PDB id:3G3E)。使用来自DrugBank(DrugBank http://www.drugbank.ca/)及在国内收集的药物代谢物及化合物的总共1463种化合物进行虚拟筛选。通过去除含有金属原子的分子及分子量在100g/mol至700g/mol范围外的分子将这些化合物缩减成子组。将总共1367种化合物的结果进行预选用于以下步骤。使用ChemAxon的mmff94(Halgren,T.A.,Merck molecular force field.1.Basis,form,scope,parameterization,and performance of MMFF94.J Comput Chem 1996,17(5-6),490-519)力场几何学上优化这些化合物(Weber,L.,JChem Base–ChemAxon.Chem World-Uk2008,5(10),65-66)。DAAO晶体结构仅保持单体。使用MGL工具包(MGL工具包,http://mgltools.scripps.edu/)在DAAO晶体结构中去除水并添加氢。在晶体复合物中去除化合物3-羟基喹啉-2(1H)-酮同时保留辅因子FAD。使用MGL工具包(MGL工具包.http://mgltools.scripps.edu/)指派化合物部分电荷。使用AutoDock Vina将总共1367种化合物嵌合成DAAO-FAD复合物(Trott,O.；Olson,A.J.,Software News and Update AutoDockVina:Improving the Speed and Accuracy of Docking with a New Scoring Function,Efficient Optimization,and Multithreading.J Comput Chem 2010,31(2),455-461)复合物，且嵌合分值是基于AMBER力场(Cornell,W.D.；Cieplak,P.；Bayly,C.1.；Gould,I.R.；Merz,K.M.；Ferguson,D.M.；Spellmeyer,D.C；Fox,T.；Caldwell,J.W.；Kollman,P.A.,Asecond generation force field for the simulation of proteins,nucleic acids,and organic molecules(第117卷,第5179页,1995).J Am Chem Soc 1996,118(9),2309-2309)。嵌合盒为在DAAO晶体结构中中心配位为(10.932,-36.407,31.470)的
正方形。穷尽值(研究花费的时间)的设定为8。选择具有最有利嵌合分值之前100种化合物来参加MDS步骤。
分子动力学模拟(MDS)
吾人针对每一化合物选择具有最低能量的结合模式且通过使用GROMACS版本4.5.2及GROMOS 53A6力场(Oostenbrink,C；Soares,T.A.；van der Vegt,N F.A.；vanGunsteren,W.F.,Validation of the 53A6 GROMOS force field.Eur Biophys J Biophy2005,34(4),273-284)实施MDS过程。将蛋白质结构置于SPC216型水分子的简单立方周期盒中，且将蛋白质与盒每一边的间的距离设为0.9nm。为维持整体静电中性及等渗条件，将Na+及Cl-离子随机放置在此溶剂化盒内。为维持适当结构并去除不利的范德华接触(van derWaals contact)，采用使用最陡下降算法的1000步能量最小化，其中步骤间差值的能量最小化收敛准则为小于1000kJ mol-1nm-1。在能量最小化后，在恒温(300K)、压力(1atm)及0.001ps(1fs)的时间步长下且每1000步记录系统的坐标，使系统经受1ns分子动力学模拟。
DAAO酶分析
根据Oguri等人(Oguri,S.,Screening of d-amino acid oxidase inhibitor bya new multi-assay method.Food chemistry 2007,100(2),616)的报导修改DAAO酶活性分析。通过使用受质D-丙胺酸反应产生的过氧化氢(H2O2)进一步与3-(4-羟基苯基)丙酸(HPPA)发生反应来量测DAAO活性。通过H2O2及过氧化物酶氧化HPPA以变成荧光二聚体，所述二聚体经量测从而代表DAAO的活性。在50mM D-丙胺酸(溶解于0.2M Tris-HCl缓冲液(pH8.3)中)中制备DAAO的受质。将100μl D-丙胺酸溶液与以下混合：4μl(100％)具有在31.36nM、94.08nM、0.28μM、0.85μM、2.54μM、7.62μM、22.86μM、68.59μM、0.21mM、0.62mM、1.85mM、5.56mM、16.67mM及50.00mM范围内的不同药物浓度的二甲亚砜(DMSO)，其中每一反应浓度中的最终DMSO浓度为0.167％。在黑色96孔板中在37℃下利用220μl反应主混合将10μl D-丙胺酸及药物混合物培育5分钟。对于110个反应分析，反应主混合含有110μl 5U/mL猪肾DAAO(Sigma-Aldrich,USA)溶液(利用0.2M Tris-HC1缓冲液(pH 8.3)溶解)、1.1mL15U/mL过氧化物酶溶液(利用0.2M Tris-HCl缓冲液(pH 8.3)溶解)、1.1mL 20mM HPPA溶液(利用0.2M Tris-HCl缓冲液(pH 8.3)溶解)及2.2ml 2M Tris-HCl缓冲液(pH 8.3)。
通过320nm下的辐照激发在405nm下量测荧光强度(Fs)。DAAO酶活性愈高，荧光强度愈高。自以下等式获得荧光抑制指示物(Fi)：Fi＝(Fs-F药物)/(FDMSO)。其中在药物混合物溶液(使用0.2M Tris HC1缓冲液,pH 8.3,不含D-丙胺酸)中量测荧光药物空白对照(F药物)。在100％DMSO溶液中量测DMSO空白对照(FDMSO)。但是，在D-氨基酸氧化酶的分析中，反应混合物中通常包括FAD，此乃因此辅助因子易于自全酶解离，本发明方法是在无FAD下实施。通过使用降低50％的DAAO活性的抑制浓度(IC50)比较DAAO抑制剂的抑制效应。通过GraphPadPrism第5版软件(GraphPad Software公司,La Jolla,CA)(GraphPad Prism 5,GraphPadsoftware公司:California,USA)藉助非线性回归模型计算IC50值。
结果
候选化合物的选择。为评价100种所选化合物在DAAO的活性位点中的可能的结合模式及相互作用型式，对这些化合物实施MSD。使用GROMOS 53A6力场(Oostenbrink,C；Soares,T.A.；van der Vegt,N.F.A.；van Gunsteren,W.F.,Validation of the 53A6GROMOS force field.Eur Biophys J Biophy 2005,34(4),273-284)及SPC216型水分子仿真复杂系统。若系统不为静电中性条件，则应添加Na+或Cl-。根据MDS的结果，分析在DAAO附近靠近每一化合物的残基。根据文献，DAAO的活性位点含有以下残基：Leu51、Gln53、Leu215、His217、Tyr 224、Tyr228、Ile230、Arg283及Gly313。(Sparey,T等人，Bioorg MedChem Lett 2008,18(11),3386-91；Kawazoe,T.等人,Biochem Bioph Res Co 2007,355(2),385-391；Duplantier,A.J.等人,J Med Chem 2009,52(11),3576-3585)。将附近在
距离内具有三个以上上文所提及残基的分子视为候选者。可自商业来源获取9个候选者从而进行测试并继续进行活体外研究。化合物的名称及结构以及其IC50列示于表1中。
实验评估。在通过320nm下的辐照激发在405nm下量测的荧光强度(Fs)下测试化合物。在利用不同的苯甲酸钠浓度培育后的DAAO酶活性显示，IC50(降低50％的DAAO活性的苯甲酸钠浓度)为约71.74μM(95％信赖区间，在62.67μM至82.13μM的范围内)。对于其他已知药物，吾人亦实施酶分析从而验证IC50。每一已知药物的IC50显示于表1中且在图2中绘制IC50的曲线。DAAO酶活性愈高，荧光强度愈高。所有9种化合物的IC50值皆位于微莫耳范围内。证实5种化合物具有抑制活性，且IC50值在1μM至10μM的范围内。5种药物再利用候选者为5-O-去甲基-奥美拉唑、奥氮平、PM-BRL 36583A、PM-BRL 36610A及度洛西汀。其中，在酶分析测试中5-O-去甲基-奥美拉唑具有最好的抑制，且IC50值为1.19μM。5-O-去甲基-奥美拉唑是奥美拉唑的代谢物，其因其在治疗消化不良、消化性溃疡疾病及胃食道逆流疾病中的治疗用途而为人所知。
表1.通过化合物的DAAO IC50对这些化合物分等级
DAAO-FAD结构下的5-O-去甲基-奥美拉唑的嵌合及相互作用研究。
先前研究指示若干抑制剂具有来自PDB的可获得DAAO-FAD-化合物晶体复合物(Schnell,E.；等人,Proc Natl Acad Sci USA 2002,99(21),13902-7)，例如，亚胺基-DOPA(Kawazoe,T.等人,Biochem Bioph Res Co 2007,355(2),385-391)、3-羟基喹啉-2(1H)-酮(Duplantier,A.J.等人,J Med Chem 2009,52(11),3576-3585)及4H-氟[3,2-b]吡咯-5-甲酸(Sparey,T.等人；Bioorg Med Chem Lett2008,18(11),3386-91)。其PDB id分别为2E82、3G3E及3CUK。根据结构分析，3种化合物位于FAD附近。关键相互作用可能源于残基Leu51、Gln53、Leu215、His217、Tyr 224、Tyr228、Ile230、Arg283及Gly313。而且，大多数关键残基可与除Leu51、Leu215及Ile230外的化合物形成氢键。(Sparey,T.等人,Biochem Bioph ResCo 2007,355(2),385-391；Duplantier,A.J.等人,J Med Chem 2009,52(11),3576-3585)
吾人分析DAAO-FAD-5-O-去甲基-奥美拉唑复合物的嵌合及MDS结果，如图1中所显示。图1(a)中展示5-O-去甲基-奥美拉唑及3-羟基喹啉-2(1H)-酮的相对结合姿态及位置(Duplantier,A.J.等人,J Med Chem 2009,52(11),3576-3585)(其是自PDB晶体结构获得)。在图1(a)中，3-羟基喹啉-2(1H)-酮在FAD附近。然而，当5-O-去甲基-奥美拉唑的苯并咪唑部分位于FAD附近时，结合姿态与上文所阐述的化合物不同。5-O-去甲基-奥美拉唑的吡啶环位于远离FAD的其他区域。在图1(b)及(d)中，残基与5-O-去甲基-奥美拉唑相互作用且包括于Leu51、Pro54、Leu56、Trpl07、His217、Asp218、Tyr224及Gly313中。其中，Leu56、Trpl07及Tyr224与5-O-去甲基-奥美拉唑形成氢键。根据这些分析，吾人表明5-O-去甲基-奥美拉唑的结合模式与3-羟基喹啉-2(1H)-酮不同，且氢键亦在复合系统中起重要作用。
实例2小鼠中的临床前药物测试
与人类研究互补，强有力的方法是使用动物模型来鉴别功能因果关系并在具有较少遗传异质性或没有遗传异质性的种群中筛选出潜在化合物。在临床前药物测试中，动物模型在医药发现及研发工作中提供重要工具(Everitt J.I,ToxicologicPathology.2015,43(1),70-7)。实际上，动物模型不仅在发现及验证潜在药物/治疗中起不可或缺的作用，且亦提供用以阐明基因与相关症状间的因果关系的可行方法(Lai,W.S等人,Current Pharmaceutical Design,2014,20(32),5139-50)。一方面，健康动物模型可有助于确保治疗潜力的质量、效能及安全性(Lebron,J.A等人,Expert Review of Vaccines,2005,4(6),855-66)。另一方面，具有特异基因的遗传改造小鼠或基因转殖小鼠的生成容许研究者研究活体内精神分裂症易感基因的生物功能。在多巴胺假设中，例如，据报导增加突触多巴胺含量的安非他命/甲基安非他命会导致正常个体的精神病或使患有精神分裂症的个体中的精神病恶化(Lieberman,J.A等人,Psychopharmacology(Berl),1987,91(4),415-433；Grant,K.M等人,Journal of Neuroimmune Pharmacology,2012,7(1),113-139)。因此，在小鼠中投与安非他命/甲基安非他命提供用以进一步研究精神分裂症的病理生理学的良好模型。然而，聚焦于多巴胺系统导致在了解精神分裂症的认知功能障碍及阴性症状的机制中的进展受限(Miyamoto,S等人,Molecular Psychiatry,2012,17,1206-1227)。因此，为改良对精神分裂症的病理学及症状学(具体而言认知及阴性症状)的了解，麸胺酸盐路径的功能障碍是所述疾病的病理生理学背后的显着机制之一(Egerton,A等人,CurrentPharmaceutical Biotechnology,2012,13(8),1500-1512；Moghaddam,B；Javitt,D,Neuropsychopharmacology,2012,37(1),4-15)。
沿相同路线，积聚研究已显示NMDA受体拮抗剂(例如苯环己派啶(PCP)及地佐环平(dizocilpine)(MK-801))可在健康个体中产生「精神分裂症样」症状(Javitt,D.C；Zukin,S.R,The American Journal of Psychiatry,1991,148,1301-1308；Krystal,J.H等人,Archives of GeneralPsychiatry,1994,51,199-214)，且在来自精神分裂症患者及具有NMDA拮抗作用的动物模型的尸体组织中观察到失调的NMDA受体亚单位(Gunduz-Bruce,H等人,Brain Research Reviews,2009,60,279-286；Lisman,J.E等人,Trends inNeurosciences,2008,31,234-242)。根据对限制PCP使用的法律限制，MK-801是较好NMDA拮抗剂，其结合于NMDA受体的离子通道内部，由此预防离子的流动。此外，新的证据亦展现MK-801能够诱导与小鼠精神分裂症相关的认知缺陷及阴性症状(Neill,J.C；Barnes等人,Pharmacology&Therapeutics,2010,128(3),419-32；Bubeníková-Valesová,V等人,Neuroscience&Biobehavioral Reviews,2008,32(5),1014-23)。值得利用MK-801小鼠精神分裂症模型来显示现象学有效性，且其适于寻找具有抗精神病药物效应的新颖物质。
小鼠中RS-D7活体内效力的结果
利用野生型(WT，健康)小鼠及药理学动物精神分裂症模型(例如MK-801及甲基安非他命小鼠精神分裂症模型)作为充分确立的动物精神分裂症模型，吾人研究RS-D7(一种DAO抑制剂)对减轻精神分裂症相关的阴性及认知缺陷的治疗潜力。已在健康对照小鼠或药理学小鼠精神分裂症模型中针对模仿精神分裂症的认知(例如，前脉冲抑制)及阴性症状(例如，蔗糖偏好性测试及热板测试)选择且实施一系列行为任务(Lai,W.S等人,CurrentPharmaceutical Design,2014,20(32),5139-50)。药理学动物精神分裂症模型部分地由于临床表现及对治疗的反应的相似性。已在不同程度的测试有效性下评估这些行为任务，从而评价小鼠中精神分裂症相关的行为缺陷。使用不同批次的雄性成年C57/B16小鼠，且在别处阐述不同行为任务的细节。
在WT小鼠模型中：
对于小鼠中的精神分裂症样阴性症状，使用热板测试来评价小鼠的基础性疼痛及伤害感受功能。与WT对照相比，在注射40mg/kg RS-D7(腹腔内)后对于55℃热板测试，小鼠第一反应(亦即，惊跳)的潜伏期有所加速且惊跳次数有所增加(图3A及图3B)。这些结果表明注射40mg/kg RS-D7可增强小鼠的伤害感受功能。
为评价小鼠的精神分裂症样认知功能，使用前脉冲抑制(PPI)来评估注射RS-D7后的小鼠的感觉运动门控功能。前脉冲抑制(PPI)是较弱预刺激(前脉冲)抑制有机体对后续强的惊人的刺激(脉冲)的反应的神经现象。在一些病症(包括患有精神分裂症的患者)中记录了PPI的缺陷。与盐水对照相比，注射20mg/kg RS-D7(腹腔内)在78dB前脉冲下诱导更大PPI(图3C)。此发现表明，20mg/kg RS-D7可增强小鼠的感觉运动门控功能。
在甲基安非他命小鼠精神分裂症模型中
甲基安非他命是有效的精神刺激剂，其可增加大脑中细胞外多巴胺的量。甲基安非他命(或安非他命)诱导的精神病模型已经充分确立且其可用于实验室动物的精神分裂症中。与DMSO及CBIO对照相比，尤其在74dB前脉冲下，注射20mg/kg RS-D7(腹腔内)可在注射甲基安非他命(3mg/kg,腹腔内)的ICR小鼠中诱导更大的PPI(图4)。此发现表明注射20mg/kg RS-D7可增强经甲基安非他命治疗的小鼠的感觉运动门控功能。
在MK-801小鼠精神分裂症模型中：
MK-801是非竞争性NMDA受体拮抗剂。注射及慢性注射MK-801可提供潜在动物模型从而模仿精神分裂症的阴性及认知症状。C57/B16小鼠接受急性MK-801(0.2mg/kg,腹腔内)投与，且选择MK-801的剂量从而在旷场中避免刻板行为。与盐水对照相比，在急性MK-801注射后观察到蔗糖摄取显着降低。有趣地，注射20mg/kg RS-D7可拯救小鼠中MK-801诱导的缺陷(图5A)。此结果表明，在蔗糖偏好性测试中急性注射RS-D7可减轻MK-801诱导的兴致缺乏。
对于热板测试，注射RS-D7亦可分别减少热板测试中MK-801诱导的潜伏期变更及反应次数(图5B及图5C)。对于PPI，如图5D中所绘示，急性MK-801注射的小鼠展现声音PPI的显着降低。重要地，注射40mg/kg RS-D7可显着减轻这些小鼠中MK-801诱导的PPI缺陷。这些结果表明RS-D7可使小鼠中MK-801诱导的功能障碍正常化。
总之，来自健康对照小鼠及药理学小鼠精神分裂症模型的所有发现皆支持，RS-D7可改良或减轻小鼠中精神分裂症相关的阴性及认知症状。
Claims (7)
1.一种化合物的用途，其用于制备治疗及/或预防个体中与DAAO抑制相关的疾病的药剂，所述化合物选自埃索美拉唑(esomeprazole)或其治疗上可接受的盐、前药或异构物，其中由DAAO抑制介导的所述疾病是精神分裂症及情感性精神分裂症的症状范围、轻度认知损害、阿兹海默病、帕金森氏病、抑郁、妥瑞氏症候群、疼痛、运动失调、抽搐、创伤后压力病症(PTSD)、强迫行为病症(OCD)、精神分裂症、痛觉缺失、失智、与神经变性疾病相关的记忆及/或认知丧失或特征在于神经变性疾病的神经元功能丧失。
2.如权利要求1的用途，其中埃索美拉唑的有效剂量为每公斤体重2mg至每公斤体重5g。
3.如权利要求1的用途，其中精神分裂症及情感性精神分裂症的这些症状范围包括阴性、认知、抑郁、阳性及一般精神病理学症状范围。
4.如权利要求1的用途，其中与DAAO抑制相关的所述疾病是轻度认知损害(MCI)、阿兹海默病、帕金森氏病或精神分裂症。
5.如权利要求1的用途，其中与DAAO抑制相关的所述疾病是疼痛、运动失调或抽搐。
6.如权利要求1的用途，其中所述药剂包含医药上可接受的载剂及/或赋形剂。
7.如权利要求1的用途，其中所述化合物经由以下方式投予：经口、非经肠途径、括静脉内、肌肉内、腹膜腔内、胸骨内、皮下、脊髓内、关节内、经十二指肠内途径、经鼻汽溶胶、吸入或经皮。
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| Publication number | Priority date | Publication date | Assignee | Title |
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| PT3137658T (pt) * | 2014-04-30 | 2022-05-05 | Univ Nat Taiwan | Uso de compostos conhecidos como inibidores do d-aminoácido oxidase |
| IL265108B2 (en) * | 2016-09-14 | 2024-03-01 | Yufeng Jane Tseng | Novel mutated benzimidazoles as D-amino acid oxidase (DAAO) inhibitors |
| CN108143734A (zh) * | 2018-02-09 | 2018-06-12 | 南京中医药大学 | 阿莫地喹及其药学上可接受的盐在制备用于治疗阿尔茨海默病的药物中的应用 |
| CN110297839B (zh) * | 2019-06-25 | 2022-04-12 | 中国人民解放军军事科学院军事医学研究院 | 药物适应症的查询方法、装置、计算机设备和存储介质 |
| IL294231A (en) * | 2021-06-23 | 2023-01-01 | Yoda Pharmaceuticals Inc | History of benzimidazole for the treatment and/or prevention of nlrp3-mediated diseases and disorders |
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| US20080004303A1 (en) * | 2005-07-29 | 2008-01-03 | Rottapharm S.P.A. | Combination of Itriglumide and Proton Pump Inhibitors in the Treatment of Gastrointestingal and Related Disorders |
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