CN113372347A - β-咔啉衍生物及其作为吲哚胺-2,3-双加氧酶1抑制剂的用途 - Google Patents
β-咔啉衍生物及其作为吲哚胺-2,3-双加氧酶1抑制剂的用途 Download PDFInfo
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- CN113372347A CN113372347A CN202110634196.XA CN202110634196A CN113372347A CN 113372347 A CN113372347 A CN 113372347A CN 202110634196 A CN202110634196 A CN 202110634196A CN 113372347 A CN113372347 A CN 113372347A
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Abstract
本发明公开了一种具有式(I)结构特征的β‑咔啉衍生物,还公开了其药学上可接受的盐、其制备方法,以及它们作为吲哚胺‑2,3‑双加氧酶1抑制剂的用途。本发明的化合物可以用于治疗吲哚胺‑2,3‑双加氧酶1介导的免疫抑制的相关疾病,包括肿瘤、自身免疫性疾病、抑郁症、焦虑症、神经变性疾病和感染性疾病。
Description
技术领域
本发明属于药物领域,具体涉及一种β-咔啉衍生物或其药学上可接受的盐、其制备方法、以及它们作为吲哚胺-2,3-双加氧酶1抑制剂的用途。
背景技术
吲哚胺-2,3-双加氧酶1(IDO1)是人体肝脏外催化色氨酸沿犬尿酸途径代谢的限速酶,它介导的色氨酸氧化分解代谢过程与机体免疫防御密切相关。在病理条件下,促炎性细胞因子(如IFN-γ、TNF-α、IL-1β和IL-6等)可以诱导IDO1上调表达,通过氧化分解色氨酸降低机体微环境中的色氨酸浓度,导致色氨酸耗竭,并且产生犬尿氨酸、3-羟基犬尿氨酸、喹啉酸等一系列代谢物,从而对机体的固有免疫和适应性免疫产生调节作用(Platten M,et al.Nat Rev Drug Discov,2019,18(5):379-401)。研究发现,IDO1介导的免疫调节作用与多种疾病密切相关,如肿瘤、病毒感染、神经变性疾病、器官移植排斥、自身免疫性疾病和神经精神疾病等(Li B,et al.Curr Med Chem,2019,26(17):3009-3025)。
IDO1在肿瘤免疫豁免及肿瘤发生过程中起着重要作用。在大多数肿瘤细胞中,高表达的IDO1产生局部的色氨酸耗竭,激活GCN2激酶,导致其下游靶标eIF-2磷酸化和衰减,诱导T细胞在G1周期增殖停滞,进而产生免疫抑制(Forouzandeh F,et al.Mol CellBiochem,2008,309(1-2):1-7)。同时,犬尿氨酸等色氨酸代谢产物具有细胞毒性,不仅能够诱导氧自由基介导T细胞凋亡,而且可以与内源性芳香烃受体(AhR)结合,导致调节性T细胞(Treg)选择性分化增殖,同时阻止辅助性T细胞17(Th17)的成熟,进而抑制树突状细胞(DC)的浸润和细胞毒性T细胞的免疫反应(Wang D,et al.Cell Mol Immunol,2017,14(5):423-431)。此外,色氨酸代谢产物还会影响巨噬细胞的转化,抑制自然杀伤细胞(NK)的增殖和功能,共同介导机体局部和/或全身性的免疫抑制作用,促进肿瘤细胞的存活和转移(ZhangJ,et al.Mol Immunol,2018,103:144-155)。因此,抑制IDO1的活性可以有效阻止肿瘤细胞周围的色氨酸降解,促进T细胞增殖,从而增强机体对肿瘤细胞的攻击能力,已成为肿瘤免疫治疗的新策略。
除了在肿瘤免疫豁免方面发挥着重要作用,IDO1的过度表达与多种神经精神疾病(如抑郁症、焦虑症、精神分裂症等)和神经变性疾病(阿尔茨海默病、帕金森病等)的发病机制密切相关。一方面,IDO1过度表达造成中枢神经系统局部色氨酸耗竭,用于合成神经递质5-羟色胺的色氨酸的量减少,从而导致5-羟色胺缺乏。另一方面,IDO1催化的色氨酸代谢产物如3-羟基犬尿氨酸和喹啉酸等具有神经毒性,共同促进神经精神疾病和神经变性疾病的发生,而且是多种心境障碍的因素(Lovelace MD,et al.Neuropharmacology,2017,112(PtB):373-388)。例如,在抑郁症患者大脑中IDO1高表达,促使色氨酸代谢过程转向犬尿氨酸途径,导致5-羟色胺的合成量减少;同时产生大量的3-羟基犬尿氨酸和喹啉酸等神经毒性分子,其中喹啉酸是内源性N-甲基-D-天冬氨酸(NMDA)受体激动剂。NMDA受体被过度激活打开Na+、Ca2+离子通道,促使胞内Ca2+浓度升高,引发下游破坏性过程,造成神经元兴奋性毒性,影响谷氨酸神经递质和多巴胺信号的传递(Hodes GE,et al.Nat Neurosci,2015,18(10):1386-1393)。由此可见,有效地抑制IDO1活性,阻止5-羟色胺的合成量减少,防止犬尿氨酸代谢途径中毒性分子的累积,这有望成为治疗抑郁症的新策略。
IDO1高表达介导的色氨酸过度代谢也存在于各种自身免疫性疾病和感染性疾病中。例如,类风湿关节炎患者的滑膜关节组织高表达IDO1,患者血清中色氨酸浓度降低,而犬尿氨酸浓度升高(Mondanelli G,et al.Autoimmun Rev,2019,18(4):334-348)。多种病毒(如HIV、HCV、流感等)感染患者,IDO1会被上调表达,促进Treg细胞增殖,而抑制Th17细胞的增殖,造成Treg/Th17细胞比例失调,导致患者的免疫抑制(Raniga K,et al.Viruses,2018,10(1):36)。
多项临床前和临床研究表明,IDO1抑制剂可以降低色氨酸代谢以及下游毒性代谢物的聚积,从而逆转IDO1介导的免疫抑制,恢复T细胞和NK细胞的增殖和功能,抑制Treg细胞的增殖,从而增强机体的免疫应答。因此,]DO1抑制剂具有广阔的临床应用前景,可用于治疗由IDO1介导的免疫抑制所引起的相关疾病,包括肿瘤、病毒感染、神经变性疾病、器官移植排斥、自身免疫性疾病和神经精神疾病等。
发明内容
本发明要解决的技术问题在于提供一种新颖的β-咔啉衍生物或其药学上可接受的盐、其制备方法,以及它们作为IDO1抑制剂的用途。本发明的化合物可以用于治疗由IDO1介导的免疫抑制所引起的相关疾病。
本发明提供了通式(I)所示的β-咔啉衍生物或其药学上可接受的盐:
其中,R1和R2其中一个为卤素,而另一个为H,所述卤素选自:F、Cl或Br;R3为含1-3个杂原子的五元杂环基或苯并五元杂环基,所述杂环基可任选地被下述相同或不相同的取代基取代,所述取代基选自:C1-C5烷基、卤素、羟基、羧基、氨基、氰基或硝基;
进一步地,具有通式(I)所示的β-咔啉衍生物或其药学上可接受的盐,其特征在于:R1和R2其中一个为F,而另一个为H;R3为噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、三氮唑基、苯并噻唑基、苯并咪唑基或苯并三氮唑基。
具体来说,通式(I)所述的β-咔啉衍生物优选自下列化合物:
下面药理实验中涉及的化合物代号等同于此处代号所对应的化合物。
本发明还提供了一种制备式(I)所示的β-咔啉衍生物的制备方法,其特征在于:
式(II)化合物和式(III)化合物通过Pictet-Spengler反应,得到式(IV)化合物,式(IV)化合物再进一步脱氢芳构化,得到式(I)化合物;其合成路线如下:
其中,R1、R2和R3的定义如前所述。
所述的式(I)化合物的药学上可接受的盐可通过一般的化学方法合成。
一般情况下,盐的制备可以通过游离碱或酸与等化学当量或过量酸(无机酸或有机酸)或碱(无机碱或有机碱)在合适的溶剂或溶剂组合物中反应制得。
本发明另外提供了式(I)所示的β-咔啉衍生物或其药学上可接受的盐在制备IDO1抑制剂中的用途,所述IDO1抑制剂用于治疗IDO1介导的免疫抑制的相关疾病患者,所述IDO1介导的免疫抑制的相关疾病为肿瘤、自身免疫性疾病、抑郁症、焦虑症、神经变性疾病、感染性疾病。
本发明还提供了式(I)所示的β-咔啉衍生物或其药学上可接受的盐在制备药物中的用途,所述药物用于治疗肿瘤、自身免疫性疾病、抑郁症、焦虑症、神经变性疾病和感染性疾病。
附图说明
图1为化合物I-5对IDO1介导的T细胞增殖抑制的影响。
图2为化合物I-5对IDO1表达的影响。
具体实施方式
为了进一步阐明本发明,下面给出一系列实施例,这些实施列可使本专业技术人员全面地理解本发明,但不以任何方式限制本发明。
实施例1
6-氟-1-(1H-吡咯-2-基)-2,3,4,9-四氢-1H-吡啶并[3,4-b]吲哚(3)的制备
在100mL圆底烧瓶中,加入5-氟吲哚乙胺(1)(1g,5.6mmol)溶于15mL二氯甲烷中,室温下搅拌加入2-吡咯甲醛(2)(637mg,6.7mmol)和三氟乙酸(0.7mL),反应混合物在室温下搅拌过夜。TLC测定原料消失,用1M氢氧化钠水溶液调节pH至9,乙酸乙酯(20mL×3)萃取,合并有机层,有机层用饱和食盐水洗涤,无水硫酸钠干燥。减压蒸干溶剂,得到淡黄色固体(7)(802mg,产率56%)。1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),11.08(d,J=6.8Hz,1H),8.18(d,J=7.9Hz,1H),7.95(d,J=5.0Hz,1H),7.63(d,J=8.2Hz,1H),6.98(t,J=2.2Hz,1H),6.75(dd,J=3.7,1.9Hz,1H),6.22(t,J=3.2Hz,1H),3.27-3.16(m,2H),2.98-2.89(m,2H);MS(ESI)m/z 256.3[M+H]+。
6-氟-1-(1H-吡咯-2-基)-9H-吡啶并[3,4-b]吲哚(I-1)的制备
在50mL圆底烧瓶中,加入化合物3(0.5g,2.0mmol)溶于10mL二甲苯中,室温搅拌下加入10%Pd/C(132mg),反应混合物加热至140℃反应10h。TLC测定原料消失,过滤,收集滤液,减压蒸馏浓缩得到黄色粗品,经硅胶色谱柱纯化(洗脱剂体积比:石油醚/乙酸乙酯=40/1~4/1),得到淡黄色固体I-1(226mg,产率46%)。1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),8.34(d,J=5.0Hz,1H),7.92(d,J=4.9Hz,1H),7.58(d,J=8.1Hz,1H),7.47(t,J=7.5Hz,1H),7.20(t,J=7.5Hz,1H),6.92(t,J=2.1Hz,1H),6.74(dd,J=3.7,1.9Hz,1H),6.21(t,J=3.2Hz,1H);MS(ESI)m/z 252.3[M+H]+。
实施例2
7-氟-1-(1H-吡咯-2-基)-9H-吡啶并[3,4-b]吲哚(I-2)的制备
参照化合物I-1的制备方法,以6-氟吲哚乙胺和2-吡咯甲醛(2)为起始原料,经两步反应制得淡黄色固体I-2(241mg,产率49%)。1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),8.38(d,J=5.1Hz,1H),7.90(d,J=4.9Hz,1H),7.54(d,J=8.1Hz,1H),7.46(t,J=7.5Hz,1H),7.18(t,J=7.4Hz,1H),6.95(t,J=2.2Hz,1H),6.75(dd,J=3.7,1.9Hz,1H),6.22(t,J=3.2Hz,1H);MS(ESI)m/z 252.3[M+H]+。
实施例3
5-(6-氟-9H-吡啶并[3,4-b]吲哚-1-基)噻唑(I-3)的制备
参照化合物I-1的制备方法,以5-氟吲哚乙胺(1)和5-噻唑甲醛为起始原料,经两步反应制得淡黄色固体I-3(529mg,产率35%)。1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),8.39(d,J=5.2Hz,1H),8.24(dd,J=11.0,6.5Hz,2H),7.89(d,J=3.2Hz,1H),7.86(d,J=83Hz,1H),7.55(t,J=7.6Hz,1H),7.26(t,J=7.5Hz,1H);MS(ESI)m/z 270.1[M+H]+。
实施例4
5-(7-氟-9H-吡啶并[3,4-b]吲哚-1-基)噻唑(I-4)的制备
参照化合物I-1的制备方法,以6-氟吲哚乙胺和5-噻唑甲醛为起始原料,经两步反应制得淡黄色固体I-4(620mg,产率41%)。1H NMR(400MHz,DMSO-d6)δ11.64(s,1H),8.36(d,J=5.1Hz,1H),8.22(dd,J=10.9,6.4Hz,2H),8.12(d,J=3.1Hz,1H),7.88(d,J=8.4Hz,1H),7.54(t,J=7.5Hz,1H),7.24(t,J=7.4Hz,1H);MS(ESI)m/z 270.1[M+H]+。
实施例5
6-氟-1-(1H-咪唑-5-基)-9H-吡啶并[3,4-b]吲哚(I-5)的制备
参照化合物I-1的制备方法,以5-氟吲哚乙胺(1)和1H-咪唑-5-甲醛为起始原料,经两步反应制得淡黄色固体I-5(623mg,产率44%)。1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),8.26(d,J=5.2Hz,1H),7.92(dd,J=15.5,10.2Hz,3H),7.83(d,J=8.2Hz,1H),7.48(t,J=7.7Hz,1H),7.18(t,J=7.5Hz,1H);MS(ESI)m/z 253.1[M+H]+。
实施例6
7-氟-1-(1H-咪唑-5-基)-9H-吡啶并[3,4-b]吲哚(I-6)的制备
参照化合物I-1的制备方法,以6-氟吲哚乙胺和1H-咪唑-5-甲醛为起始原料,经两步反应制得淡黄色固体I-6(566mg,产率40%)。1H NMR(400MHz,DMSO-d6)δ11.40(s,1H),8.24(d,J=5.1Hz,1H),8.16(d,J=7.8Hz,1H),7.90(dd,J=15.4,10.0Hz,2H),7.81(d,J=8.1Hz,1H),7.44(t,J=7.5Hz,1H),7.16(t,J=7.5Hz,1H);MS(ESI)m/z 253.1[M+H]+。
实施例7
6-氟-1-(1H-1,2,3-三唑-5-基)-9H-吡啶并[3,4-b]吲哚(I-7)的制备
参照化合物I-1的制备方法,以5-氟吲哚乙胺(1)和1H-1,2,3-三唑-5-甲醛为起始原料,经两步反应制得淡黄色固体I-7(412mg,产率29%)。1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),8.59(s,1H),8.22(d,J=7.8Hz,1H),8.10(d,J=4.9Hz,1H),7.85(d,J=8.4Hz,1H),7.52(t,J=7.6Hz,1H),7.23(t,J=7.4Hz,1H);MS(ESI)m/z 254.3[M+H]+。
实施例8
7-氟-1-(1H-1,2,3-三唑-5-基)-9H-吡啶并[3,4-b]吲哚(I-8)的制备
参照化合物I-1的制备方法,以6-氟吲哚乙胺和1H-1,2,3-三唑-5-甲醛为起始原料,经两步反应制得淡黄色固体I-8(469mg,产率33%)。1H NMR(400MHz,DMSO-d6)δ11.41(s,1H),8.61(s,1H),8.38(d,J=5.3Hz,1H),8.12(d,J=5.0Hz,1H),7.85(d,J=8.4Hz,1H),7.51(t,J=7.6Hz,1H),7.18(t,J=7.3Hz,1H);MS(ESI)m/z 254.3[M+H]+。
实施例9
6-(6-氟-9H-吡啶并[3,4-b]吲哚-1-基)苯并[d]噻唑(I-9)的制备
参照化合物I-1的制备方法,以5-氟吲哚乙胺(1)和苯并[d]噻唑-6-甲醛为起始原料,经两步反应制得淡黄色固体I-9(538mg,产率30%)。1H NMR(400MHz,DMSO-d6)δ12.22(s,1H),8.86(d,J=6.2Hz,1H),8.62(d,J=6.3Hz,1H),8.30(d,J=8.3Hz,1H),8.18-8.14(m,1H),7.95(dd,J=6.9,1.3Hz,1H),7.79(dd,J=8.2,7.0Hz,1H),7.54-7.48(m,2H),7.42(d,J=8.4Hz,1H);MS(ESI)m/z 320.2[M+H]+。
实施例10
6-(7-氟-9H-吡啶并[3,4-b]吲哚-1-基)苯并[d]噻唑(I-10)的制备
参照化合物I-1的制备方法,以6-氟吲哚乙胺和苯并[d]噻唑-6-甲醛为起始原料,经两步反应制得淡黄色固体I-10(717mg,产率40%)。1H NMR(400MHz,DMSO-d6)δ12.23(s,1H),8.79(d,J=6.1Hz,1H),8.61(d,J=6.3Hz,1H),8.17-8.12(m,1H),8.10(d,J=2.6Hz,1H),7.92(dd,J=6.7,1.3Hz,1H),7.75(dd,J=8.0,6.9Hz,1H),7.67-7.61(m,1H),7.40(d,J=8.2Hz,1H),7.36(dd,J=9.0,2.5Hz,1H);MS(ESI)m/z 320.2[M+H]+。
实施例11
1-(1H-苯并[d]咪唑-6-基)-6-氟-9H-吡啶并[3,4-b]吲哚(I-11)的制备
参照化合物I-1的制备方法,以5-氟吲哚乙胺(1)和1H-苯并[d]咪唑-6-甲醛为起始原料,经两步反应制得淡黄色固体I-11(713mg,产率42%)。1H NMR(400MHz,DMSO-d6)δ11.23(s,1H),8.41(d,J=4.9Hz,1H),8.21(dd,J=8.8,2.2Hz,1H),8.01-7.94(m,3H),7.89(d,J=8.9Hz,1H),7.76(d,J=4.9Hz,1H),7.54(dd,J=7.1,5.0Hz,1H),7.22(ddd,J=8.1,7.1,2.7Hz,1H);MS(ESI)m/z 303.1[M+H]+。
实施例12
1-(1H-苯并[d]咪唑-6-基)-7-氟-9H-吡啶并[3,4-b]吲哚(I-12)的制备
参照化合物I-1的制备方法,以6-氟吲哚乙胺和1H-苯并[d]咪唑-6-甲醛为起始原料,经两步反应制得淡黄色固体I-12(848mg,产率50%)。1H NMR(400MHz,DMSO-d6)δ11.21(s,1H),8.77(d,J=5.1Hz,1H),8.21(dd,J=8.8,2.2Hz,1H),8.14(dd,J=8.1,5.0Hz,1H),7.99(d,J=2.1Hz,1H),7.96(d,J=6.0Hz,1H),7.89(d,J=9.0Hz,1H),7.77(d,J=5.1Hz,1H),7.20(dd,J=7.9,2.1Hz,1H),7.11(td,J=8.2,2.3Hz,1H);MS(ESI)m/z 303.1[M+H]+。
实施例13
1-(1H-苯并[d][1,2,3]三唑-6-基)-6-氟-9H-吡啶并[3,4-b]吲哚(I-13)的制备
参照化合物I-1的制备方法,以5-氟吲哚乙胺(1)和1H-苯并[d][1,2,3]三唑-6-甲醛为起始原料,经两步反应制得淡黄色固体I-13(511mg,产率30%)。1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),8.78(d,J=4.9Hz,1H),8.09(dd,J=9.3,2.2Hz,1H),7.98(dd,J=8.1,2.8Hz,1H),7.92(d,J=9.3Hz,1H),7.87(d,J=2.2Hz,1H),7.76(d,J=4.9Hz,1H),7.54(dd,J=7.1,5.0Hz,1H),7.22(ddd,J=8.1,7.1,2.7Hz,1H);MS(ESI)m/z 304.1[M+H]+。
实施例14
1-(1H-苯并[d][1,2,3]三唑-6-基)-7-氟-9H-吡啶并[3,4-b]吲哚(I-14)的制备
参照化合物I-1的制备方法,以6-氟吲哚乙胺(1)和1H-苯并[d][1,2,3]三唑-6-甲醛为起始原料,经两步反应制得淡黄色固体I-14(698mg,产率41%)。1H NMR(400MHz,DMSO-d6)δ11.34(s,1H),8.77(d,J=5.1Hz,1H),8.14(dd,J=8.1,5.0Hz,1H),8.09(dd,J=9.3,2.2Hz,1H),7.92(d,J=9.3Hz,1H),7.87(d,J=2.2Hz,1H),7.77(d,J=5.1Hz,1H),7.20(dd,J=7.9,2.2Hz,1H),7.11(td,J=8.1,2.3Hz,1H);MS(ESI)m/z 304.1[M+H]+。
实施例15
体外人重组IDO1酶抑制活性的测试分析
实验材料和主要仪器:
酶标仪(品牌:Bio-Tek型号:SYNERGY H1),离心机(上海安亭飞鸽离心机TGL-16G),人重组IDO1蛋白(Sigma),人源过氧化氢酶Catalase(Sigma),L-色氨酸(BBI生命科学有限公司),L-犬尿氨酸(Sigma),磷酸钾(生工生物工程股份有限公司),亚甲基蓝(上海麦克林生化科技有限公司),抗坏血酸(博格隆生物技术有限公司),三氯乙酸(TCA,上海麦克林生化科技有限公司),超纯水由超纯水系统制备、其他试剂均为分析纯。
实验方法:
(1)测试原理
人体内IDO1酶是肝脏外催化色氨酸沿犬尿氨酸途径代谢的起始和限速酶。IDO1酶催化L-色氨酸转化为N-甲酰-L-犬尿氨酸,再在三氯乙酸作用下降解为L-犬尿氨酸。采用荧光分光光度法,间接检测L-犬尿氨酸的含量来判断待测化合物对IDO1酶的抑制程度。
(2)标准曲线的制定
用缓冲溶液(缓冲溶液配制:50mM磷酸钾,10mM抗坏血酸,10μM亚甲基蓝,pH调至6.5)配制400μM,300μM,200μM,150μM,100μM,75μM,50μM,37.5μM,25μM,18.75μM,12.5μM,9.375μM,6.25μM和4.6875μM的L-犬尿氨酸标准溶液,取100μL与等体积20mg/mL对二甲氨基苯甲醛的乙酸溶液混合,使用酶标仪在480nm处检测吸光度,制作标准线性曲线关系。
(3)IDO1和Catalase酶工作液的配制
反应体系中L-色氨酸为50μM/L,需要IDO1酶量:50/0.00006=833333.33U/L=0.833U/μL(1X)即1.04U/μL(1.25X)。需将IDO1浓缩液稀释192.3倍(1.04U/μL×80μL=83.3U,即需IDO1浓缩液0.4165μL)。Catalase酶保护IDO1酶免受氧化损伤,需将其浓缩液稀释300倍。在0℃条件下,将缓冲溶液3.96mL加入到10mL冷冻管中,再依次加入人重组IDO1酶浓缩液20.8μL和Catalase酶浓缩液13.3μL,混合均匀(微小体积改变已忽略)。
(4)实验操作步骤
设置空白组,阴性组和测试组,每组2个复孔。以下操作除加热和孵育过程,其他均在0℃条件下进行。在PCR管中先加入酶工作液80μL×2,再加入10μL×2受试化合物(0.5mM,5%DMSO)和10μL×2L-色氨酸(0.5mM)。其中空白组不含酶和受试化合物,阴性组不含受试化合物,其他条件平行。将PCR管置于37℃下孵育1个小时。然后,加入40μL三氯乙酸(30%w/v),在50℃下孵育0.5个小时,使N-甲酰基犬尿氨酸转化为犬尿氨酸。将反应体系在5000rpm离心3分钟,取上清液100μL移至96孔板中,每孔加入等体积对二甲氨基苯甲醛的乙酸溶液(20mg/mL,现配现用)。混合溶液用Bio-Tek酶标仪(型号:SYNERGY H1)在480nm处检测吸光度,由公式%=[(阴性组-测试组)/(阴性组-空白组)]×100计算受试化合物50μM浓度下的IDO1酶抑制率。若在该浓度下,受试化合物的IDO1抑制率大于80%,则将其依次稀释8个浓度(按1∶1等比例稀释),检测不同浓度下的IDO1酶抑制率,使用GraphPad软件拟合量效曲线,计算其半数抑制浓度IC50值。
实验结果:
实验结果如表1所示。结果表明,本发明化合物对IDO1酶的活性具有显著的抑制作用,其中,化合物I-5的体外IDO1酶抑制活性最强(IC50=3.70±2.46μM)。同时,采用上述检测方法测得阳性对照药PF-06840003的IDO1酶抑制作用的IC50值为0.37±0.04μM,与文献值(IC50=0.41μM)相当。由此可见,本发明的体外人重组IDO1酶抑制活性的测试结果可靠。
表1.本发明化合物对IDO1酶的抑制活性。
实施例16
化合物I-5对IDO1介导的T细胞增殖抑制的影响
人神经胶质瘤细胞U87在IFN-γ的刺激下,可以高表达蛋白IDO1,通过犬尿氨酸途径降解L-色氨酸,使其浓度降低,影响了T细胞的成熟和活化,而其代谢产物也对T细胞具有杀伤作用。同时,经过这一途径的代谢产物对T细胞的分化也具有影响,可以促使T细胞分化成为Treg细胞,对肿瘤的免疫逃逸起到促进作用。
实验方法:T淋巴细胞预先用CFSE染料标记,与U87细胞共培养(1×106个T淋巴细胞/孔;2×105个U87细胞/孔),该体系中还含有150U/mL的IL-2,100ng/mL的抗-CD3和60ng/mL的IFN-γ。随后,阳性对照药1-L-MT(1μM)和不同浓度的化合物I-5(40nM,200nM,500nM,1μM)分别加入到培养板中。共培养48h,采用流式细胞仪检测FL1和FL2通道细胞的增殖情况。
实验结果:
实验结果如图1所示,化合物I-5能够逆转IDO1+U87细胞刺激的T细胞增殖抑制,在相同浓度下,效果优于1-L-MT。
实施例17
化合物I-5对IDO1表达的影响
实验方法:
U87细胞以2×105每孔的密度接种到细胞培养板上培养,于37℃,5%CO2条件下培养12小时。空白对照组(只加培养基),模型组1(加入IFN-γ),模型组2(加入IFN-γ、对应阳性药1-L-MT),药物处理组(加入IFN-γ、对应化合物I-5),于37℃,5%CO2条件下培养24小时,收集细胞,Western blot检测IDO1表达。
实验结果:
实验结果如图2所示,化合物I-5不影响U87细胞中IDO1的表达,说明化合物I-5是通过抑制IDO1的活性来逆转IDO1介导的免疫抑制。
本发明不局限于上述实施例所述的具体技术方案,凡采用等同替换形成的技术方案均为本发明要求的保护范围。
Claims (6)
2.权利要求1所述的β-咔啉衍生物或其药学上可接受的盐,其特征在于:R1和R2其中一个为F,而另一个为H;R3为噻吩基、吡咯基、噁唑基、噻唑基、咪唑基、吡唑基、三氮唑基、苯并噻唑基、苯并咪唑基或苯并三氮唑基。
5.权利要求1-3任一项所述的β-咔啉衍生物或其药学上可接受的盐在制备吲哚胺-2,3-双加氧酶1抑制剂中的用途,所述吲哚胺-2,3-双加氧酶1抑制剂用于治疗吲哚胺-2,3-双加氧酶1介导的免疫抑制的相关疾病患者,所述吲哚胺-2,3-双加氧酶1介导的免疫抑制的相关疾病为肿瘤、自身免疫性疾病、抑郁症、焦虑症、神经变性疾病和感染性疾病。
6.权利要求1-3任一项所述的β-咔啉衍生物或其药学上可接受的盐在制备药物中的用途,所述药物用于治疗肿瘤、自身免疫性疾病、抑郁症、焦虑症、神经变性疾病和感染性疾病。
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---|---|---|---|---|
CN115093400A (zh) * | 2021-09-18 | 2022-09-23 | 重庆华森制药股份有限公司 | AhR抑制剂及其用途和制备方法 |
CN116354959A (zh) * | 2023-03-10 | 2023-06-30 | 石河子大学 | 一种N-N桥连噻唑单元的β-咔啉衍生物及其制备方法、应用 |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101735215A (zh) * | 2008-11-14 | 2010-06-16 | 中国药科大学 | β-咔啉环取代脲类raf激酶抑制剂及其制备方法和用途 |
CN101932325B (zh) * | 2007-11-30 | 2014-05-28 | 新联基因公司 | Ido抑制剂 |
-
2021
- 2021-06-07 CN CN202110634196.XA patent/CN113372347B/zh active Active
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN101932325B (zh) * | 2007-11-30 | 2014-05-28 | 新联基因公司 | Ido抑制剂 |
CN101735215A (zh) * | 2008-11-14 | 2010-06-16 | 中国药科大学 | β-咔啉环取代脲类raf激酶抑制剂及其制备方法和用途 |
Non-Patent Citations (1)
Title |
---|
YONGCHENG SONG ET AL.: ""β-Carbolines as Specific Inhibitors of Cyclin-Dependent Kinases"", 《BIOORGANIC & MEDICINAL CHEMISTRY LETTERS》, vol. 12, pages 1129 - 2232 * |
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CN115093400A (zh) * | 2021-09-18 | 2022-09-23 | 重庆华森制药股份有限公司 | AhR抑制剂及其用途和制备方法 |
CN115093400B (zh) * | 2021-09-18 | 2023-09-05 | 北京华森英诺生物科技有限公司 | AhR抑制剂及其用途和制备方法 |
CN116354959A (zh) * | 2023-03-10 | 2023-06-30 | 石河子大学 | 一种N-N桥连噻唑单元的β-咔啉衍生物及其制备方法、应用 |
CN116354959B (zh) * | 2023-03-10 | 2024-04-19 | 石河子大学 | 一种N-N桥连噻唑单元的β-咔啉衍生物及其制备方法、应用 |
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