CN112469442B - 用于治疗肾脏疾患的化合物 - Google Patents
用于治疗肾脏疾患的化合物 Download PDFInfo
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- CN112469442B CN112469442B CN201980048869.4A CN201980048869A CN112469442B CN 112469442 B CN112469442 B CN 112469442B CN 201980048869 A CN201980048869 A CN 201980048869A CN 112469442 B CN112469442 B CN 112469442B
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- 238000002415 sodium dodecyl sulfate polyacrylamide gel electrophoresis Methods 0.000 description 1
- IXMINYBUNCWGER-UHFFFAOYSA-M sodium;4-propoxycarbonylphenolate Chemical compound [Na+].CCCOC(=O)C1=CC=C([O-])C=C1 IXMINYBUNCWGER-UHFFFAOYSA-M 0.000 description 1
- 239000012453 solvate Substances 0.000 description 1
- 238000000527 sonication Methods 0.000 description 1
- LXMSZDCAJNLERA-ZHYRCANASA-N spironolactone Chemical compound C([C@@H]1[C@]2(C)CC[C@@H]3[C@@]4(C)CCC(=O)C=C4C[C@H]([C@@H]13)SC(=O)C)C[C@@]21CCC(=O)O1 LXMSZDCAJNLERA-ZHYRCANASA-N 0.000 description 1
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- 239000006190 sub-lingual tablet Substances 0.000 description 1
- 229940098466 sublingual tablet Drugs 0.000 description 1
- 239000007940 sugar coated tablet Substances 0.000 description 1
- 239000011593 sulfur Substances 0.000 description 1
- 150000003467 sulfuric acid derivatives Chemical class 0.000 description 1
- 229960003491 sulodexide Drugs 0.000 description 1
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- 238000012353 t test Methods 0.000 description 1
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- QJJXYPPXXYFBGM-SHYZHZOCSA-N tacrolimus Natural products CO[C@H]1C[C@H](CC[C@@H]1O)C=C(C)[C@H]2OC(=O)[C@H]3CCCCN3C(=O)C(=O)[C@@]4(O)O[C@@H]([C@H](C[C@H]4C)OC)[C@@H](C[C@H](C)CC(=C[C@@H](CC=C)C(=O)C[C@H](O)[C@H]2C)C)OC QJJXYPPXXYFBGM-SHYZHZOCSA-N 0.000 description 1
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- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- 150000003892 tartrate salts Chemical class 0.000 description 1
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- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 1
- 125000003718 tetrahydrofuranyl group Chemical group 0.000 description 1
- 125000003831 tetrazolyl group Chemical group 0.000 description 1
- 125000005305 thiadiazolinyl group Chemical group 0.000 description 1
- 125000001113 thiadiazolyl group Chemical group 0.000 description 1
- 239000003451 thiazide diuretic agent Substances 0.000 description 1
- 125000001984 thiazolidinyl group Chemical group 0.000 description 1
- 230000008719 thickening Effects 0.000 description 1
- 239000002562 thickening agent Substances 0.000 description 1
- 125000001544 thienyl group Chemical group 0.000 description 1
- 125000004568 thiomorpholinyl group Chemical group 0.000 description 1
- 239000012049 topical pharmaceutical composition Substances 0.000 description 1
- 125000005490 tosylate group Chemical group 0.000 description 1
- 229960002051 trandolapril Drugs 0.000 description 1
- 238000012546 transfer Methods 0.000 description 1
- 230000001052 transient effect Effects 0.000 description 1
- 230000014616 translation Effects 0.000 description 1
- 238000004627 transmission electron microscopy Methods 0.000 description 1
- 125000001425 triazolyl group Chemical group 0.000 description 1
- 125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- YFTHZRPMJXBUME-UHFFFAOYSA-N tripropylamine Chemical compound CCCN(CCC)CCC YFTHZRPMJXBUME-UHFFFAOYSA-N 0.000 description 1
- GPRLSGONYQIRFK-MNYXATJNSA-N triton Chemical compound [3H+] GPRLSGONYQIRFK-MNYXATJNSA-N 0.000 description 1
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- C07D213/60—Heterocyclic compounds containing six-membered rings, not condensed with other rings, with one nitrogen atom as the only ring hetero atom and three or more double bonds between ring members or between ring members and non-ring members having three double bonds between ring members or between ring members and non-ring members having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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Abstract
本公开涉及用于治疗肾脏疾患,特别是慢性肾病、肾小球疾病或蛋白尿性肾病诸如Alport综合征、局灶节段性肾小球硬化和糖尿病肾病的ABCA1诱导剂化合物。
Description
技术领域
本公开涉及用于治疗肾脏疾患,特别是用于治疗慢性肾病、肾小球疾病或蛋白尿性肾病例如Alport综合征、局灶节段性肾小球硬化和糖尿病肾病的ABCA1诱导剂化合物。
背景技术
慢性肾病(CKD)导致需要透析或者肾脏移植的终末期肾病(ESRD),是一种日渐普遍的流行病,影响了全球数百万计的患者(Bello AK等人,JAMA,317:1864,2017)。虽然在世界范围内,糖尿病仍是ESRD最常见的病因,但其他病因,例如高血压、囊性肾病和肾小球肾炎促进了很大部分的ESRD流行(USRDS数据库)。这些疾患中有许多可能表现为蛋白尿,其范围从轻度蛋白尿到重度肾病范围蛋白尿,重度蛋白尿是进展为ESRD的主要风险因素。虽然肾脏替代策略增加了患者的死亡率,但当前的治疗策略只能减缓但不能阻止CKD的进展。一些干预研究未能证明其有效性。这在很大程度上是由于目前正在测试的许多干预研究针对的是肾脏疾病的晚期阶段,而不是早期发病过程。
目前,现有的治疗策略包括使用血管紧张素转换酶(ACE)抑制剂和血管紧张素受体阻滞剂(ARB),这些药剂有助于减少蛋白尿和减缓肾小球硬化的进展。到目前为止,蛋白尿肾病患者已经接受了ACE抑制剂的治疗,其中包括,但不限于:贝那普利、西拉普利、依那普利(Vasotec)、福辛普利(蒙诺)、赖诺普利(Zestril,Prinivil)、培哚普利、雷米普利、喹那普利(Accupril)、群多普利,以及ARB包括坎地沙坦(Atacand)、依普沙坦、厄贝沙坦、氯沙坦(科素亚)、替米沙坦、缬沙坦。用于FSGS中的蛋白尿治疗的唯一获批药物是ACTHar。其他免疫抑制剂的许多标签外使用也被应用于一些蛋白尿性肾病,例如FSGS。这些免疫抑制剂包括强的松(或一般类固醇)、利妥昔单抗,钙调神经磷酸酶抑制剂(环孢霉素和他克莫司)、雷帕霉素、阿巴西普、mychophenolate mophetyl。例如辅酶Q10、鱼油、维生素D衍生物、无麸质饮食、别嘌呤醇、螺内酯、LDL单采、血浆除去法等其他策略也正在被使用。
然而,许多此类治疗均基于病例系列,不受随机研究支持,经常伴有严重的副作用,且未针对特定的致病机制进行设计。此外,对这些治疗的响应是无法预测的。因此,当前所用药物无法提供一种安全并有效的治疗。更具体地,长期以来对于新型药物的需求未得到满足,该新型试剂用于患有肾小球疾患和更广泛的慢性肾病患者的预防或治疗。
发明内容
发明人进一步研究了治疗慢性肾病患者,特别是原发性肾小球疾病,如Alport综合征和FSGS,以及继发性肾小球疾病,如糖尿病肾病(DKD)的新治疗策略。他们已证明某些吡啶甲酰胺化合物在此类肾脏疾病的治疗中具有非常有希望的效果。
已将吡啶甲酰胺描述为ATP结合盒转运子A1蛋白的小分子诱导剂(ABCA1诱导剂)。例如,在国际专利申请公开号WO 2011/029827、WO 2012/032018、WO 2013/037703和WO2014180741中描述了此种吡啶甲酰胺。
因此,本公开涉及一种用于治疗肾脏疾病的化合物,其中所述化合物是一种ABCA1诱导剂化合物。
在某一具体实施例中,此ABCA1诱导剂化合物由以下结构式I表示:
其中
A1和A2中的一者为N并且A1和A2中的另一者为CH;
R1选自由以下项组成的组:C1-7-烷基;C3-7-环烷基;C3-7-环烷基-C1-7-烷基;C1-7-烷氧基-C1-7-烷基;卤素-C1-7-烷基;杂环基-C1-7-烷基,其中,所述杂环基基团未被取代或被氧代基取代;和杂芳基-C1-7-烷基,其中,所述杂芳基基团未被取代或被低级烷基单取代或双取代;
R2和R6彼此独立地为氢或卤素;
R3和R5彼此独立地选自由以下项组成的组:氢、C1-7-烷基、C1-7-烷氧基、卤素、卤素-C1-7-烷基、卤素-C1-7-烷氧基和氰基;
R4选自由以下项组成的组:氢、C1-7-烷基、C1-7-烷氧基、卤素、卤素-C1-7-烷基、卤素-C1-7-烷氧基、氨基和氰基;
R7选自由以下项组成的组:C1-7-烷基;C3-7-环烷基,所述环烷基未被取代或被羟基取代;杂环基,所述杂环基具有3至7个环原子,包含选自N、O和S的一个、二个或三个杂原子且未被取代或被羟基或氧代基取代;苯基,其中,苯基未被取代或被选自由以下项组成的组的一个或两个基团取代:C1-7-烷基、羟基、C1-7-烷氧基、氰基、卤素和卤素-C1-7-烷基;和杂芳基,其中,杂芳基未被取代或被选自由以下项组成的组的一个或两个基团取代:C1-7-烷基、羟基、C1-7-烷氧基、氰基、卤素和卤素-C1-7-烷基),并且
G选自由以下项组成的组:-(CH2)m-,其中m选自0或1;和-NR8,其中R8为氢或C1-7-烷基,
和其药用盐。
在具体实施例中,G为键且R7为C3-7-环烷基,所述环烷基未被取代或被羟基取代。
在可与先前的实施例组合的具体实施例中,R7是被羟基取代的环己基。
在可与先前的实施例组合的具体实施例中,R2和R6各自为氢,R4为卤素,以及R3和R5中的一者为卤素并且R3和R5中的另一者为氢。
在可与先前的实施例组合的具体实施例中,R1是卤素-C1-7-烷基。通常,R1可选自-CF3、-CHF2、-CH2Cl、-CH2CF3、-CH(CF3)2、-CF2-CF3。
在某一优选实施例中,如本文所述使用的ABCA1诱导剂化合物是6-(3,4-二氯苯基)-N-[(1R,2R)-2-羟基环己基]-5-(2,2,2-三氟乙氧基)吡啶-2-甲酰胺。
在另一优选实施例中,如本文所述使用的ABCA1诱导剂化合物为5-(3,4-二氯-苯基)-N-((1R,2R)-2-羟基-环己基)-6-(2,2,2-三氟-乙氧基)-烟酰胺。
在可与先前的实施例组合的具体实施例中,该ABCA1诱导剂化合物在慢性肾病、原发性和继发性肾小球疾病或蛋白尿疾病的治疗中是有用的。通常,此类ABCA1诱导剂化合物可用于治疗Alport综合征、局灶节段性肾小球硬化、或糖尿病肾病。
在可与先前的实施例组合的具体实施例中,将如本文所述使用的ABCA1诱导剂化合物配制为口服施用。
在另一具体实施例中,将如本文所述使用的ABCA1诱导剂化合物配制为用于局部、鼻内、眼内、静脉内、肌内、皮下、玻璃体内、鞘内或经皮施用。
本公开还涉及一种治疗需要其的受试者的肾脏疾病的方法,包括施用治疗有效量的如上文所定义的ABCA1诱导剂。
在此方法的具体实施例中,所述ABCA1诱导剂可以同时地、分别地或依序地与治疗有效量的另一种试剂,例如血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂组合施用。
附图说明
图1.在Balb/c小鼠的ADR诱导的肾病中测试化合物最佳剂量的实验设计。将12mg/kg剂量的多柔比星(ADR,阿霉素)经尾静脉注射注入30只雌性Balb/c小鼠。接受生理盐水的5只小鼠的基线组。然后,将ADR注射的小鼠分为6组,每组五只,共七个实验组。从第二天开始,通过口服管饲每天一次施用化合物,持续5周。每周收集尿液并每周记录体重。于ADR注射后35天,在处死时收集血液和肾皮质。
图2:在Balb/c小鼠的ADR诱导的肾病中测试化合物的实验设计。将12mg/kg剂量的多柔比星(ADR,阿霉素)经尾静脉注射注入雌性Balb/c小鼠。接受生理盐水的5只小鼠的对照组。将ADR注射的雌性小鼠分为五组,每组6只。如所示的,从第二天开始,通过口服管饲每天一次施用溶媒或化合物,持续4周。每周收集尿液并每周记录体重。于ADR注射后28天,在处死时收集血液和肾皮质。
图3.在分化的人类足细胞中的化合物毒性。分化的人类足细胞经0μM(溶媒)、1μM、5μM和10μM的Cpd A、Cpd C、Cpd D、Cpd E、Cpd F和Cpd G处理18h。使用Promega CytoTox测定试剂盒评估细胞毒性。以普通培养基(空心柱)处理为基线。细胞毒性信号标准化至活性信号,消除细胞数量差异造成的偏差。将所有的处理与溶媒处理的细胞进行比较。仅在CpdA和Cpd C的浓度超过10uM时发现显著毒性。单因素ANOVA,n=3个独立实验,Dunett检验,*p<0.5,***p<0.001。
图4.用Cpd C、Cpd A和Cpd G处理增加分化的足细胞中ABCA1的表达和胆固醇外排。
如所示的,用溶媒(0.1%DMSO)或化合物将分化的人类足细胞处理18h,然后测量ABCA1的表达、定位及参与胆固醇外排的情况。(a)全细胞裂解液中ABCA1和GAPDH蛋白质免疫印迹显示LXR激动剂(Cpds C、E和D)对ABCA1表达具有强的诱导作用,10μMABCA1诱导剂Cpds A和G对ABCA1表达有中度诱导作用。(b-e)Cpd C、Cpd A和Cpd G增加ABCA1在质膜上的表达。如所示的,用溶媒或化合物C、A和G将分化的人类足细胞处理18h后进行细胞分级。(b)全细胞裂解液中ABCA1和GAPDH蛋白质免疫印迹显示Cpd A(5uM)和Cpd G(10uM)处理后ABCA1表达中度增加。(c-e)针对ABCA1、Na+/K+ATP酶泵和MEK对质膜、微粒体和细胞质收集的级分进行印迹和探测。(f-h)在分化的足细胞中,Cpd C、A和G增加ApoA1介导的胆固醇外排。如所示的,将载有[3H]-胆固醇的分化足细胞与化合物孵育18h。在与或不与ApoA1一起细胞孵育18h后,计算ApoA1介导的胆固醇外排。数据报告为至少三个独立实验的平均值和s.d.。单因素ANOVA,Dunett检验,*P<0.05%,**P<0.01%。
图5.选择减轻ADR诱导的肾脏损害的化合物的最佳剂量。
(a-e)用cpds按所示剂量处理5周期间,ADR注射小鼠中的白蛋白尿。ADR注射2-3周后,小鼠产生大量的蛋白尿,在30mg/Kg剂量的CpdA(b)和100mg/Kg的Cpd G(e)处理的小鼠中缓解了该情况。
(f-j).ADR注射小鼠的特征在于是在ADR注射后二至三周体重显著下降,在接受30mg/kg Cpd A或100mg/kg Cpd G的小鼠中,这一表型部分减弱。所示结果代表各组的平均值和SE。单因素ANOVA n=5,Dunett检验,*P<0.05%。
图6.ABCA1诱导剂Cpd A和Cpd G显著降低ADR注射小鼠的白蛋白尿和体重下降。注射有ADR(12mg/Kg)的小鼠接受溶媒、LXR激动剂Cpd C或最佳剂量的ABCA1诱导剂(Cpd A和Cpd G),每日一次,持续28天。每周测量一次白蛋白尿和体重。(a)4周处理后的白蛋白尿。(b)体重下降,表现为每只小鼠处理4周后体重与注射ADR前一天体重的差值。基线组(为非ADR注射小鼠),如左侧所示,反映了无肾脏损伤的表型。条代表每个处理组的中位数和范围。采用Mann Whitney检验将所有组与接受溶媒组进行比较(n=8,*P<0.05%,**P<0.01%,****P<0.0001%)。
图7.取自经溶媒或100mg/Kg/日的Cpd G处理4周的ADR注射的动物肾脏的PAS和HE切片的病理检查。病理学家评估了球性硬化的%(A);节段性硬化的%(B);足细胞肥大(C);足细胞增生(D);管状物小囊肿(E)和间质性炎(F)。标度值表示如下:0:0%;0.5+:1-10%;1+:11-25%;2+:26-50%;3+:51-75%;4+>75%。使用Mann Whitney检验比较Cpd G处理组样品与溶媒处理组样品(n=7;*P<0.05%)。
图8.用溶媒或100mg/Kg的Cpd G处理生理盐水或ADR注射小鼠以28天。用ORO对肾皮质切片进行染色并检测脂滴沉积。来自健康基线组(A)、溶媒(B)和100mg/Kg/日Cpd G(C)处理的ADR注射组的切片的代表性图。
图9.Cpd G减少ADR注射小鼠的肾组织中酯化胆固醇的积累。从用溶媒或Cpd G处理28天的ADR注射小鼠肾皮质中提取的脂质用于胆固醇酯、总胆固醇和甘油三酯的测定。每种脂类的量均标准化至标本中存在的总蛋白质。肾组织中的(a)酯化胆固醇、(b)总胆固醇含量和(c)甘油三酯含量。左侧所示为未接受ADR注射的动物,并且代表无肾脏损伤诱导时的基线值。使用Mann Whitney双尾检验比较Cpd G和溶媒处理组,n=8;****P<0.0001%。(d-f).每只小鼠白蛋白尿与其肾皮质中脂类的量的相关性。发现与胆固醇酯(d)有强的相关性,但与总胆固醇(e)和甘油三酯(f)无相关性。Pearson检验.n=10
图10.在ADR注射后一天,用溶媒或100mg/Kg的Cpd处理12mg/Kg ADR注射的动物。照片拍摄于使用溶媒(A-B)和100mg/Kg的Cpd G(C-D)处理20天后。
图11.用Cpd G处理Col4A3 KO小鼠延迟向终末期肾脏疾病的进展。用溶媒或100mg/Kg的Cpd G处理4周龄129-Col4A3 KO小鼠,持续4周。56天后实验结束时,测量体重,收集点尿和血液并分析肾脏的脂质沉积情况。用溶媒或Cpd G处理的KO小鼠的(a)白蛋白尿、(b)血清肌酐、(c)血尿素氮和(d)体重。(e)每组PAS-染色的肾脏切片的代表图,(f)系膜扩张定量(于e.同龄Col4a3+/+小鼠(wt)中所述的PAS-染色肾脏切片经盲性病理分析后进行)列于左侧,以反映无慢性肾病的表型。(g)于6周龄开始接受溶媒或Cpd G(100mg/Kg/日)4周的129-Col4a3 KO小鼠的存活曲线。水平条代表每组的中位数。使用双尾Mann Whitney检验计算各组间统计学差异,n=4,*P<0.05%,**P<0.01%。
图12.利用Db/+,db/db溶媒处理的小鼠和db/db ABCA1诱导剂(化合物A)处理的小鼠进行如下分析:(A)中为在处理开始时(14周)、处理2周后(16周)以及处理4周后(18周)处死时测定白蛋白与肌酐比率;测定小鼠血清中的血尿素氮(BUN)并以mg/dL表示(B);肾皮质胆固醇含量(每mg蛋白质中nmol胆固醇的倍数变化)以总胆固醇(TC)、游离胆固醇(FC)及胆固醇酯(CE)的形式存在(C);BUN和CE间的相关性(D);通过WT1抗体测定每个肾小球横切面足细胞数(E)并定量(F);采用PAS染色肾皮质切片对肾小球系膜扩张评分(G)并定量(H);通过TEM图像测定足细胞足突消退(I)并定量(J)。单因素ANOVA后使用Tukey检验*p<0.05,**p<0.01,***p<0.001,****p<0.0001。
图13.Cpd G减少酯化胆固醇在肾皮质中的积累测定8周龄Col4A3KO(于4周龄时开始接受共28天的溶媒或Cpd G处理)的肾皮质中(a)酯化胆固醇(CE)、(b)总胆固醇(TC)和(c)甘油三酯含量(TG)。每种脂类的含量均标准化至总蛋白质含量。这项研究中还纳入了一组野生型同胞小鼠(空心圆圈)。水平条代表每组的中位数。使用双尾Mann Whitney检验计算统计学差异,n=8,*P<0.05,**P<0.001。
具体实施方式
发明人已证明ABCA1诱导剂化合物在肾脏疾患,特别是肾小球疾病,例如Alport综合征或局灶节段性肾小球硬化,或其他慢性肾病,如糖尿病肾病的治疗中具有非常有希望的效果。该化合物不仅可以减少这些疾患中的蛋白尿,而且可以改善肾功能并预防终末期肾病的发展。
根据本公开使用的ABCA1诱导剂化合物
如本文所用,术语“ABCA1诱导剂化合物”是指能够间接或直接诱导ATP结合盒转运子蛋白(ABCA1)的表达水平或活性的化合物。已知该转运子ABCA1是细胞胆固醇和磷脂稳态的主要调节因子。特别地,ABCA1介导胆固醇和磷脂外排到缺脂性载脂蛋白(apo-A1和apoE),其然后形成新生的高密度脂蛋白(HDL)。例如,已经在WO2012/031817中描述了确定ABCA1蛋白在细胞中上调的体外测定。那些体外测定包括但不限于如WO2012/031817所述的胆固醇外排测定或荧光apo-A1结合测定。
已将吡啶甲酰胺描述为ATP结合盒转运子A1蛋白的小分子诱导剂(ABCA1诱导剂)。例如,在国际专利申请公开号WO 2011/029827、WO 2012/032018、WO 2013/037703和WO2014/180741中描述了此种吡啶甲酰胺。
在某一优选实施例中,本公开涉及式I的ABCA1诱导剂化合物的使用,
其中,A1和A2中的一者为N并且A1和A2中的另一者为CH;
R1选自由以下项组成的组:C1-7-烷基;C3-7-环烷基;C3-7-环烷基-C1-7-烷基;C1-7-烷氧基-C1-7-烷基;卤素-C1-7-烷基;杂环基-C1-7-烷基,其中该杂环基基团未被取代或被氧代基取代;和杂芳基-C1-7-烷基,其中该杂芳基基团未被取代或被低级烷基单取代或双取代;
R2和R6彼此独立地为氢或卤素;
R3和R5彼此独立地选自由以下项组成的组:氢、C1-7-烷基、C1-7-烷氧基、卤素、卤素-C1-7-烷基、卤素-C1-7-烷氧基和氰基;
R4选自由以下项组成的组:氢、C1-7-烷基、C1-7-烷氧基、卤素、卤素-C1-7-烷基、卤素-C1-7-烷氧基、氨基和氰基;
R7选自由以下项组成的组:C1-7-烷基;C3-7-环烷基,所述环烷基未被取代或被羟基取代;杂环基,所述杂环基具有3至7个环原子,包含选自N、O和S的一个、二个或三个杂原子且未被取代或被羟基或氧代基取代;苯基,其中,苯基未被取代或被选自由以下项组成的组的一个或两个基团取代:C1-7-烷基、羟基、C1-7-烷氧基、氰基、卤素和卤素-C1-7-烷基;和杂芳基,其中,杂芳基未被取代或被一组或两组选自包含以下项的组取代:C1-7-烷基、羟基、C1-7-烷氧基、氰基、卤素和卤素-C1-7-烷基,以及
G选自由以下项组成的组:-(CH2)m-,其中,m选自0或1;和-NR8,其中,R8为氢或C1-7-烷基、其药用盐。
术语“低级烷基”或“C1-7-烷基”,在单独或组合下指具有1至7个碳原子的直链或支链烷基、特别地指具有1至6个碳原子的直链或支链烷基和更特别地指具有1至4个碳原子的直链或支链烷基。直链和支链C1-7烷基的实例是甲基、乙基、丙基、异丙基、丁基、异丁基、叔丁基、异构戊基、异己基和异庚基,特别地是甲基、乙基、丙基、异丙基和叔丁基。
术语“低级烷氧基”或“C1-7-烷氧基”指的是基团R’-O-,其中R’是低级烷基,且术语“低级烷基”已于上文给出意义。低级烷氧基的实例是甲氧基、乙氧基、正丙氧基、异丙氧基、正丁氧基、异丁氧基、仲丁氧基和叔丁氧基,特别是甲氧基。
术语“低级烷氧基烷基”或“C1-7-烷氧基-C1-7-烷基”指的是上文所定义的低级烷基基团,其被上文所定义的低级烷氧基基团单取代或多取代。低级烷氧基烷基的实例是例如-CH2-O-CH3、-CH2-CH2-O-CH3、-CH2-O-CH2-CH3和本文具体例示的基团。更特别地,低级烷氧基烷基是甲氧基乙基。
术语羟基表示基团-OH。
术语“环烷基”或“C3-7-环烷基”表示由3至7个碳原子组成的饱和碳环基团,如环丙基、环丁基、环戊基、环己基或环庚基。
术语“低级环烷基烷基”或“C3-7-环烷基-C1-7-烷基”指的是上文所定义的低级烷基基团,其中低级烷基基团的至少一个氢原子被上文所定义的环烷基基团取代。在特别关注的低级环烷基烷基基团中存在环丙基甲基。
术语“卤素”指的是氟、氯、溴和碘,其中特别关注的是氟、氯和溴。更特别地,卤素指的是氟和氯。
术语“低级卤素烷基”或“卤素-C1-7-烷基”指的是被卤素,特别是氟或氯,更特别的是氟单取代或多取代的低级烷基基团。低级卤素烷基的实例是例如-CF3、-CHF2、-CH2Cl、-CH2CF3、-CH(CF3)2、-CF2-CF3、-CH2-CH2-CF3、-CH(CH3)-CF3和本文具体例示的基团。特别关注的是三氟甲基(-CF3)和2,2,2-三氟乙基(-CH2CF3)基团。
术语“低级卤素烷基”或“卤素-C1-7-烷氧基”指的是上文所定义的低级烷氧基基团,其中低级烷氧基基团的至少一个氢原子被卤素原子,特别是氟或氯,更特别地是氟取代。特别关注的低级卤素烷基基团是三氟甲氧基、二氟甲氧基、氟甲氧基和氯甲氧基,更特别是三氟甲氧基。
术语氨基表示基团-NH2。
术语“氰基”表示基团-CN。
术语“叠氮基”表示基团-N3。
术语“杂芳基”指的是芳香族5-或6-元环,其可包括选自N、O和S的一个、二个或三个原子。杂芳基基团的实例是例如呋喃基、吡啶基、吡嗪基、嘧啶基、哒嗪基、噻吩基、异噁唑基、噻唑基、异噻唑基、噻二唑基、噁唑基、咪唑基、吡唑基、三唑基、噁二唑基、噁三唑基、四唑基、五唑基或吡咯基。术语“杂芳基”还包括双环基团,其包含由两个5-或6-元环,其中一个或两个环是芳香族且可含有选自氮、氧或硫的一个、两个或三个原子,例如喹啉基、异喹啉基、噌啉基、吡唑并[1,5-a]吡啶基、咪唑并[1,2-a]吡啶基、喹噁啉基、苯并噻唑基、苯并三唑基、吲哚基、吲唑基和3,4-二氢-2H-吡啶并[3,2-b][1,4]噁嗪基。特别关注的杂芳基基团是异噁唑基、吡唑基、噁二唑基、噻唑基、吡啶基、哒嗪基、嘧啶基和吡嗪基。更特别地,杂芳基是吡啶基和哒嗪基。
术语“低级杂芳基烷基”或“杂芳基-C1-7-烷基”指的是上文所定义的低级烷基基团,其中低级烷基基团的至少一个氢原子被上文所定义的杂芳基基团取代。
术语“杂环基”指的是饱和的或部分饱和的3-、4-、5-、6-或7-元环,其可包括选自N、O和S的一个、两个或三个杂原子。杂环基环的实例包括哌啶基、哌嗪基、氮杂环丁烷基、氮杂环庚烯基、吡咯烷基、吡唑烷基、咪唑啉基、咪唑烷基、噁唑烷基、异噁唑烷基、吗啉基、噻唑烷基、异噻唑啉基、环氧乙烷基、噻二唑基啉基、氧杂环丁烷基、二氧戊环基、二氢呋喃基、四氢呋喃基、二氢吡喃基、四氢吡喃基和硫代吗啉基。特别关注的是哌啶基和四氢吡喃基。
术语“低级杂环基烷基”或“杂环基-C1-7-烷基”指的是上文所定义的低级烷基基团,其中低级烷基基团的至少一个氢原子被上文所定义的杂环基基团取代。
术语“氧代基”是指该杂环基或杂芳基环的碳原子可以被=O取代,因此是指该杂环基或杂芳基环可包含一个或多个碳基(-CO-)基团。
在使用式(I)化合物的具体实施例中,G为键且R7为C3-7-环烷基,所述环烷基未被取代或被羟基取代。例如,R7是环己基,其可被或不可被羟基取代。
在具体实施例中,R2和R6各自为氢。
在具体实施例中,R4是卤素,例如氯或氟,并且R3和R5中的一者为卤素,例如氯或氟,并且R3和R5中的另一者为氢。
在具体实施例中,R1是卤素-C1-7-烷基,通常,R1选自-CF3、-CHF2、-CH2Cl、-CH2CF3、-CH(CF3)2、-CF2-CF3。
具体化合物的实例是下述化合物:
在具体实施例中,如本文所述的用于治疗肾脏疾病的化合物选自由以下项组成的组:5-(3,4-二氯-苯基)-N-((1R,2R)-2-羟基-环己基)-6-(2,2,2-三氟-乙氧基)-烟酰胺和6-(3,4-二氯苯基)-N-[(1R,2R)-2-羟基环己基]-5-(2,2,2-三氟乙氧基)吡啶-2-甲酰胺。
本公开还涵盖式(I)的化合物、其互变异构体、对映异构体、非对映异构体、外消旋体或混合物,或水合物、溶剂化物、药用盐,用于肾脏疾病。
术语“药用盐”指的是那些保留游离碱或游离酸的生物学有效性和特性,且不具有任何不希望的自身特性的盐。这些盐用无机酸和有机酸形成,其中无机酸如盐酸、氢溴酸、硫酸、硝酸、磷酸等,特别是盐酸,其中有机酸如甲酸、乙酸、丙酸、乙醇酸、丙酮酸、草酸、马来酸、丙二酸、水杨酸、琥珀酸、富马酸、酒石酸、柠檬酸、苯甲酸、肉桂酸、扁桃酸、甲基磺酸、乙基磺酸、对甲苯磺酸、水杨酸、N-乙酰基半胱氨酸等。因此,在具体实施例中,“药用盐”包括式I的化合物的乙酸盐、溴化物、氯化物、甲酸盐、延胡索酸盐、马来酸盐、甲磺酸盐、硝酸盐、草酸盐、磷酸盐、硫酸盐、酒石酸盐和甲苯磺酸盐。此外,药用盐可以通过向游离酸中添加无机碱或有机碱来制备。衍生自无机碱的盐包括但不限于,钠盐、钾盐、锂盐、铵盐、钙盐、镁盐等。衍生自有机碱的盐包括但不限于伯胺、仲胺和叔胺、取代胺(包括天然出现的取代胺)、环胺和碱性离子交换树脂(例如异丙胺、三甲胺、二乙胺、三乙胺、三丙胺、乙醇胺、二乙胺、赖氨酸、精氨酸、N-乙基哌啶、哌啶、哌嗪等)的盐。式I的化合物也可以以两性离子或水合物的形式存在。特别地式I的化合物的药用盐可以是盐酸盐。
式I的化合物合成方法的实例如WO2011/029827、WO 2012/032018、WO 2013/37703和WO2014/180741所述。制备化合物G的示例性方法如WO2011/029827中所述,且制备化合物A的示例性方法如WO2014/180741中所述。
式I的化合物的使用方法
已经发现,式I的化合物(通常为实例中所述的化合物A和G),或其药用盐在肾脏疾病的治疗中是有用的。
如本文所述,术语“肾脏疾病”是指肾脏的正常生理和功能中的任何改变。该术语包括但不限于疾病和病症,如肾脏移植;肾病;原发性肾小球病、局灶节段性肾小球硬化包括伴局灶性节段性肾小球硬化的散发性特发性激素耐药性肾病综合征、微小病变肾病、膜性GN、C3肾小球病变、有肾脏意义的球蛋白病、IgA肾病、慢性肾病(CKD);肾小球肾炎;遗传性疾病,如多囊肾病;急性和慢性间质性肾炎、中美洲肾病;肾病综合征;肾炎综合征、终末期肾病(ESRD);急性和慢性肾功能衰竭;间质性疾病;肾炎;硬化,组织和/或血管的硬结或硬化,由以下原因引起,包括例如,因疾病或损伤而引起的炎症;肾纤维化和瘢痕形成;肾脏相关的增生性疾患;以及其它原发或继发的肾源性病症。
肾脏疾病通常也可定义为“肾病”或“肾病变”。术语“肾病”或“肾病变”涵盖所有肾脏中的临床病理变化,其可引起肾脏纤维化和/或肾小球疾病(例如,肾小球硬化或肾小球肾炎)和/或慢性肾功能不全,且能导致终末期肾病和/或肾功能衰竭。
本公开的一些方面涉及用于预防和/或治疗高血压肾病、糖尿病肾病和其它类型的肾病的组合物及其用途,其中糖尿病肾病例如糖尿病性肾疾患,其它类型的肾病例如镇痛剂肾病、免疫介导的肾小球病(例如,IgA肾病或Berger病、狼疮肾炎)、缺血性肾病、HIV相关的肾病、膜性肾病、肾小球肾炎、肾小球硬化、放射性造影剂引起的肾病、中毒性肾病、镇痛剂诱发的肾毒性、顺铂相关性肾病、移植肾病,以及其它形式的肾小球异常或损伤,或肾小球毛细血管损伤(管状纤维化)。在一些实施例中,术语“肾病”或“肾病变”具体指的是疾患或病症,其中受试者的尿液中存在蛋白质(即,蛋白尿)和/或存在肾功能不全,本文中也指蛋白尿性肾脏疾患。
在一些实施例中,受试者患有白蛋白尿或蛋白尿。与白蛋白尿相关的典型性疾患包括,但不限于,慢性肾病、增生性肾小球肾炎(例如,免疫球蛋白A肾病、膜增生性肾小球肾炎、系膜增生性肾小球肾炎、抗肾小球基底膜病、肾脏小血管炎、狼疮肾炎、冷球蛋白相关性肾小球肾炎、细菌性心内膜炎、过敏性紫癜、感染后肾小球肾炎,或丙型肝炎),和非增生性肾小球肾炎(例如,膜性肾小球肾炎、微小病变肾病、原发性局灶节段性肾小球硬化(FSGS)、纤维性肾小球肾炎、免疫曲张性肾小球肾炎、淀粉样变、Alport综合征、高血压性肾硬化、多发性骨髓瘤的轻链疾病和继发性局灶性肾小球硬化)。
在本文所述所有实施例中,受试者可能要接受某些测试以评估肾功能。这些测试包括,但不限于,测量受试者血尿素氮;测量受试者血液中的肌酐;测量受试者血液中的肌酐清除率;测量受试者的蛋白尿;测量受试者的白蛋白:肌酐的比例;测量受试者的肾小球滤过率;以及测量受试者的排尿量。
如本文所述,术语“治疗”或“处理”表示逆转、缓解、抑制此术语适用的疾病或病症的进展,或预防此术语适用的疾病或病症,或逆转、缓解、抑制此术语适用的疾病或病症的进展,或预防一个或多个此术语适用的疾患或病症的症状。因此,在另一个方面,本公开也涉及式I的化合物(通常为实例中所述的化合物A和G)或其药用盐,用于以下用途:减少、抑制或消除与肾脏疾患相关的症状,包括但不限于,减少蛋白尿、减缓蛋白尿的增加、减缓尿白蛋白肌酐比值(UACR)的增加、降低UACR、减缓UAER的增加、减少UAER、降低白蛋白尿、减缓白蛋白尿的增加、增加肾小球足细胞密度、阻止或减缓肾小球基底膜(GBM)增厚、减少肾小球面积、降低肾间质巨噬细胞的数量、减少或减缓肾组织的纤维化、停止或减少肾脏的炎症、停止或减少巨噬细胞诱导的对肾脏的损害、增加或正常化估算的肾小球滤过率(eGFR)、减弱eGFR的下降、降低肾小球硬化症、阻止或减少肾小球细胞外基质的增生、停止或减少透明质团的沉积、停止或降低肾小球上皮增生病变(EPHLs),以及停止或减少淋巴细胞浸润。
因此,本公开还涉及药物组合物,其包含如上文所定义的式I的化合物和药用的载体和/或佐剂,用于治疗如上文所定义的肾脏疾病。
特别地,本公开涉及如上文所定义的一种药物组合物,其用于治疗和/或预防肾脏疾病,包括慢性肾病、蛋白尿和/或肾小球疾病。优选用途涉及Alport综合征、局灶节段性肾小球硬化和糖尿病肾病。
在另一个实施例中,本发明涉及一种用于治疗和/或预防肾脏疾病的方法,该方法包括向有此需要的受试者施用治疗有效量的式I的化合物。此类肾脏疾病的实例包括慢性肾病、蛋白尿和/或肾小球疾病。优选的是用于治疗和/或预防Alport综合征、局灶节段性肾小球硬化和糖尿病肾病的方法。
此外,本公开涉及如上文所述的式I的化合物(通常为实例中所述的化合物A和G),或其药用盐用于制备治疗和/或预防肾脏疾病的药物的用途。此类肾脏疾病的实例包括慢性肾病、蛋白尿和/或肾小球疾病。特别关注的是,如上文所述的式I的化合物用于制备治疗和/或预防Alport综合征、局灶节段性肾小球硬化和糖尿病肾病的药物的用途。
药物组合物的形式、施用途径、剂量和方案理所当然地取决于待治疗的病症、病情的严重程度、患者的年龄、体重和性别等。
本公开的药物组合物可配制为用于局部、口服、鼻内、眼内、静脉内、肌内或皮下等的施用。优选地,本公开的药物组合物可配制为用于口服施用。
在某一具体实施例中,本公开的药物组合物可配制为用于玻璃体内、鞘内或经皮施用。
该药物组合物可以采取片、丸、胶囊、半固体、粉末、持续释放制剂、溶液、悬浮液、乳剂、糖浆、酏剂、气雾剂,或任意其它适当的组合物的形式;且包括至少一种如上文所定义的式I的化合物。
在某一具体实施例中,口服制剂是片、口腔分散片、胶囊、溶液、贴剂、舌下含片、鼻喷雾剂或口腔喷剂。在某一子实施例中,制剂是为如上文所述式I的化合物的持续释放制备的。
由于易于施用,片和胶囊是最具优势的口服单位剂型,在这种情况下显然使用固体药物载体。若需要,可以是使用标准工艺的糖衣片或肠溶衣片。可将对该片或丸进行包衣,以提供一种具有延长作用优势的剂型。例如,该片或丸可包括内剂型和外剂型组分,后者以包膜的形式覆盖在前者之上。肠溶层可将这两种组分分开,肠溶层用于抵抗在胃中的分解并允许内部组分完整地进入十二指肠或用于延迟释放。各种各样的材料可以用于这种肠溶层或包衣,此类材料包括使用诸如虫胶、鲸蜡醇和乙酸纤维素的许多聚合酸。
适用的载体材料不仅是无机载体材料,也是有机载体材料。因此,例如,乳糖、玉米淀粉或其衍生物、滑石、硬脂酸或其盐可作为载体材料用于片、包衣片、糖衣丸和硬明胶胶囊。适用于软明胶胶囊的载体材料是,例如,植物油、蜡、脂肪以及半固态和液态多元醇(然而,依据活性成分的特性,软明胶胶囊中可能不需要载体。)适用于制备溶液和糖浆剂的载体材料是,例如,水、多元醇、蔗糖、转化糖等。适用于注射液的载体材料是,例如,水、醇、多元醇、甘油和植物油。适用于栓剂的载体材料是,例如,天然或硬化油、蜡、脂肪和半液态或液态多元醇。适用于局部制剂的载体材料是甘油酯、半合成和合成甘油酯、氢化油、液体蜡、液体石蜡、液体脂肪醇、固醇、聚乙二醇和纤维素衍生物。
常用的稳定剂、防腐剂、润湿剂和乳化剂、增稠剂、增味剂、改变渗透压的盐、缓冲物质、增溶剂、着色剂、掩蔽剂和抗氧化剂都可以作为药物佐剂。
施用剂量可以作为各种参数的函数加以调整,特别是作为所使用的施用方式的函数、有关的病理的函数或替代地期望的治疗持续时间的函数。须知,化合物的适当剂量,以及包含化合物的组合物,可能因患者而异。最佳剂量的确定通常涉及平衡治疗益处水平与本文所述治疗的任何风险或有害副作用。所选剂量水平取决于多种因素,包括但不限于:特定化合物的活性、施用途径、施用时间、化合物的排泄率、治疗持续时间、其他药物、化合物和/或组合使用的材料,以及年龄、性别、体重、病症、总体健康状况和患者之前的病史。化合物的量和施用途径最终将由医师判定,虽然一般来说,剂量应达到作用部位的局部浓度,以达到预期的效果,而不造成实质性的有害的或有毒的副作用。
约1至100mg,特别是约1至50mg的日剂量可以用于成年患者。据疾病的严重程度和精确的药代动力学特征,该化合物可以施用一个或几个每日剂量单位,例如1至3个剂量单位。
在一个特定实施例中,根据本公开使用的化合物以20至800mg/日的每日剂量施用。
在一个特定实施例中,根据本公开使用的化合物以200mg/日的每日剂量施用。
根据本公开使用的药物组合物便利地含有约1至200mg,优选是75至100mg的式I的化合物(通常为实例中所述的化合物A和G),或其药用盐。给药方案可根据式I的化合物的特定药代动力学特性定制。
在一个特定实施例中,式I的化合物(通常为实例中所述的化合物A和G),或包含其的药物组合物的施用为每日一次、每日两次、每日三次、每三日一次、每周一次、每两周一次,或每月一次。优选地,剂量周期选自每日两次、每日一次和每隔一日一次。
在另一个特定实施例中,式I的化合物(通常为实例中所述的化合物A和G),或其药用盐的负荷剂量方案为前7天、14天和30天的剂量加倍。
在另一个特定实施例中,根据本公开使用的药物组合物可能含有约20至800mg,优选是50至400mg,更优选是约200mg的式I的化合物(通常为实例中所述的化合物A和G),或其药用盐。
在另一个特定实施例中,根据本公开使用的式I的化合物(通常为实例中所述的化合物A和G),或其药用盐,每日剂量是20至800mg/日,优选地每日剂量是约200mg/日。
此外,根据本公开使用的式I的化合物也可与另一种试剂同时地、分别地或依序地组合或联合,用于预防或治疗肾脏疾病或相关的疾患或并发症。此类已知化合物的实例包括但不限于:血管紧张素转换酶(ACE)抑制剂药物(例如,卡托普利马来酸依那普利/>福辛普利/>赖诺普利/>培哚普利/>喹那普利/>trandanalopril/>洛汀新、莫昔普利、雷米普利);RAS阻滞剂;血管紧张素受体阻滞剂(ARB)(例如,奥美沙坦、厄贝沙坦、氯沙坦、缬沙坦、坎地沙坦、依普沙坦、替米沙坦等);蛋白激酶C(PKC)抑制剂(例如,鲁伯斯塔);AGE依赖性通路抑制剂(例如,氨基胍、ALT-946、pyrodoxamine(pyrododorin)、OPB-9295、alagebrium);抗炎剂(例如,clyclooxigenase-2抑制剂、麦考酚酯、咪唑立宾、己酮可可碱)、GAG(例如,舒洛地特(美国专利号5,496,807));吡哆胺(美国专利号7,030,146);内皮素拮抗剂(例如,SPP 301)、COX-2抑制剂、PPAR-γ拮抗剂和其它化合物如氨磷汀(用于顺铂相关性肾病)、卡托普利(用于糖尿病性肾病)、环磷酰胺和利妥昔单抗(用于特发性膜性肾病)、硫代硫酸钠(用于顺铂相关性肾病)、曲尼司特、环糊精及其衍生物(例如羟丙基-β-环糊精)等(Williams and Tuttle(2005),Advances in Chronic Kidney Disease,12(2):212-222;Giunti et al.(2006),Minerva Medica,97:241-62)。在具体实施例中,用于组合或联合的已知化合物,包括但不限于,巴多索隆或mir-21的寡核苷酸抑制剂(mir-21 antagomir)。
在另一个具体实施例中,用于组合或联合的已知化合物,包括,维生素D衍生物、抗高血糖试剂(例如,SGLT2抑制剂、GLP1激动剂、DPP4抑制剂)、抗高胆固醇试剂(例如,他汀类、烟酸、贝特类药、PCSK9抑制剂、依泽替米贝)。
如本文所述,术语“组合”是指一种单位剂型中的固定剂量组合,非固定剂量组合或用于组合施用的部分的试剂盒,其中式I的化合物和一种或多种组合伴侣(例如ACE抑制剂药物或ARB药物)可以在同一时间独立施用或在时间间隔内分别施用,尤其是在这些时间间隔允许组合伴侣表现出合作,例如协同效应的情况下。
术语“固定剂量组合”是指活性成分以单一实体或剂量的形式同时地施用于患者。
术语“非固定剂量组合”是指活性成分(例如式I的化合物和一个或多个组合伴侣(例如,一种ACE抑制剂药物或ARB药物))作为分开的实体同时地或依序地都施用于患者,无具体时间限制,其中此种施用提供了两种化合物在患者体内的治疗有效水平。
此外,本文所述方法还包括与至少一种其他治疗剂共施用,该其它治疗试剂用于治疗与肾脏疾病并发症直接或间接相关的另一种疾病,该疾病包括但不限于:血脂异常、高血压、肥胖、神经病变、炎症和/或视网膜病变。上述其它治疗试剂包括但不限于:皮质类固醇;免疫抑制药物;抗生素;抗高血压和利尿药物(例如噻嗪类利尿药和ACE抑制剂或β肾上腺素拮抗剂);降血脂剂,例如胆酸螯合剂树脂、考来烯胺、考来替泊、烟酸,更特别是用来降低胆固醇和甘油三酯的药品和药物(例如,贝特类药(例如, ))和HMG-CoA抑制剂(/> 等);烟酸;和维生素D。
如本文所述,术语“共施用”或“组合施用”意图涵盖向其中的单个受试者施用所选组合伴侣,并旨在包括那些不需要用相同施用途径或在同一时间施用的试剂的治疗方案。
术语“联合治疗有效的”指治疗试剂可在此时间间隔内分别施用(以时间交错的方式,特别是以特定次序的方式),以显示(最好是协同的)相互作用(即联合治疗效果)。
因此,本公开还涉及一种药物,包括:
(i)如上文所述的式I的化合物,通常为实例中所述的化合物A或G,其与选自由以下项组成的组的化合物组合或联合:
(ii)血管紧张素转换酶(ACE)抑制剂药物;RAS阻滞剂;血管紧张素受体阻滞剂(ARB);蛋白激酶C(PKC)抑制剂;AGE依赖性通路抑制剂;抗炎剂、GAG;吡哆胺(美国专利号7,030,146);内皮素拮抗剂、COX-2抑制剂、PPAR-γ拮抗剂和其它化合物如氨磷汀(用于顺铂相关性肾病)、卡托普利(用于糖尿病性肾病)、环磷酰胺(用于特发性膜性肾病)、硫代硫酸钠(用于顺铂相关性肾病)或曲尼司特、环糊精及其衍生物(例如羟丙基-β-环糊精),和
(iii)药用的载体和/或佐剂。
如本文所述,术语“药物”指一种药物组合物,或几个药物组合物的组合,其在一种或多种赋形剂存在的情况下含有一种或多种活性成分。
本公开进一步涉及如上文所述的式I的化合物与选自由以下项组成的组的化合物同时地、依序地或分别地使用:血管紧张素转换酶(ACE)抑制剂药物;RAS阻滞剂;血管紧张素受体阻滞剂(ARB);蛋白激酶C(PKC)抑制剂;AGE依赖性通路抑制剂;抗炎剂、GAG;吡哆胺(美国专利号7,030,146);内皮素拮抗剂、COX-2抑制剂、PPAR-γ拮抗剂和其它化合物如氨磷汀(用于顺铂相关性肾病)、卡托普利(用于糖尿病性肾病)、环磷酰胺(用于特发性膜性肾病)、硫代硫酸钠(用于顺铂相关性肾病)、曲尼司特或环糊精及其衍生物(例如羟丙基-β-环糊精)、维生素D衍生物、抗高血糖试剂和抗高胆固醇试剂。本公开还涉及一种治疗和/或预防肾脏疾病的方法,该方法包括施用治疗有效量的根据式I的化合物与治疗有效量的选自由以下项组成的组的化合物组合或联用:血管紧张素转换酶(ACE)抑制剂药物;RAS阻滞剂;血管紧张素受体阻滞剂(ARB);蛋白激酶C(PKC)抑制剂;AGE依赖性通路抑制剂;抗炎剂、GAG;吡哆胺(美国专利号7,030,146);内皮素拮抗剂、COX-2抑制剂、PPAR-γ拮抗剂和其它化合物如氨磷汀(用于顺铂相关性肾病)、卡托普利(用于糖尿病性肾病)、环磷酰胺(用于特发性膜性肾病)、硫代硫酸钠(用于顺铂相关性肾病)、曲尼司特,或环糊精及其衍生物(例如羟丙基-β-环糊精)、维生素D衍生物、抗高血糖试剂和抗高胆固醇试剂。
在下述实例中,式(I)化合物已在至少3种不同肾脏疾病,即,Alport综合征、局灶节段性肾小球硬化和糖尿病肾病的体内动物模型中进行了测试,其反映了此类化合物在一些肾脏疾患中的有希望的治疗效果。
实例
ABCA1诱导剂化合物的制备
化合物列表:
已在WO2014/180741中描述了上述化合物及其合成方法。
G(5-(3,4-二氯-苯基)-N-((1R,2R)-2-羟基-环己基)-6-(2,2,2-三氟-乙氧基)-烟酰胺)化合物的制备
该化合物由5-溴-6-氯-3-吡啶羧酸、2,2,2-三氟乙醇、(1R,2R)-2-氨基-环己醇和3,4-二氯苯硼酸按照WO 2011/029827中实例3的步骤制备而成。MS463.079,465.077(M+H)+。
A6-(3,4-二氯苯基)-N-[(1R,2R)-2-羟基环己基]-5-(2,2,2-三氟乙氧基)吡啶-2-甲酰胺化合物的制备
按照WO 2014/180741中描述的步骤制备化合物A,步骤如下:
a)6-氯-2-(3,4-二氯苯基)-3-氟吡啶
在一个100mL的四颈烧瓶中,将2,6-二氯-3-氟吡啶(765mg,4.61mmol,Eq:1.00,CAS登记号52208-50-1)和钾(3,4-二氯苯基)三氟硼酸盐(1.21g,4.61mmol,Eq:1.00,CAN850623-68-6)与二氧六环(23mL)和水(13mL)合并。加入2M Na2CO3(6.91mL,13.8mmol,Eq:3),然后加入PdCl2(DPPF)-CH2Cl2加合物(169mg,230μmol,Eq:0.05,CAS登记号95464-05-4)。反应混合物3倍脱气并用氩气净化,然后在过夜搅拌条件下加热至60℃。将反应混合物冷却至室温,倒入50mL H2O中,然后用叔丁基-甲醚(2x100mL)萃取。有机层经H2O/盐水洗涤、合并,用Na2SO4干燥,并真空浓缩。利用快速层析法纯化粗物质两次(硅胶,70g,5%至20%二氯甲烷的庚烷溶液),以得到540mg为白色半固体的标题化合物。
b)6-氯-2-(3,4-二氯苯基)-3-(2,2,2-三氟乙氧基)吡啶
在一个25mL的梨形烧瓶中,将上述制备的6-氯-2-(3,4-二氯苯基)-3-氟吡啶(530mg,1.44mmol,Eq:1.00)与DMSO(8mL)合并。加入KOH(118mg,2.1mmol,Eq:1.46)和2,2,2-三氟乙醇(211mg,153μl,2.11mmol,Eq:1.47)并在室温下反应2h。将混合物倒入30mL H2O中,然后用叔丁基-甲醚(2x40mL)萃取。有机层经H2O/盐水洗涤、合并,用Na2SO4干燥,并真空浓缩。利用快速层析法纯化粗产物(硅胶,70g,5%至20%EtOAc的庚烷溶液),以得到为无色液体的444mg标题化合物;MS(ESI)356.3,358.3,360.3(M+H)+。
c)甲基6-(3,4-二氯苯基)-5-(2,2,2-三氟乙氧基)吡啶-2-羧酸叔丁酯
在一个35mL的高压釜中,将上述制备的6-氯-2-(3,4-二氯苯基)-3-(2,2,2-三氟乙氧基)吡啶(437mg,1.22mmol,Eq:1.00)溶解在5mL MeOH中。用氩气隔绝氧气和湿分,加入PdCl2(DPPF)-CH2Cl2加合物(75.2mg,92μmol,Eq:0.083,CAS登记号95464-05-4),然后加入三乙胺(233mg,321mL,2.31mmol,Eq:2.31)。然后,用CO冲洗反应器三次,加压至70bar,然后在110℃下进行20h的羰基化反应。在冷却和释放压力后,于真空浓缩粗反应混合物。然后将残余物在AcOEt/H2O中重新溶解并转移到一个分液漏斗中。水层用乙酸乙酯反萃取,有机层经H2O和盐水洗涤、合并,用Na2SO4干燥,并真空浓缩。快速层析法(硅胶,70g,10%至40%EtOAc的庚烷溶液)最终输出327mg为白色固体的标题产物;MS(ESI)380.4,382.4(M+H)+。
d)6-(3,4-二氯苯基)-5-(2,2,2-三氟乙氧基)吡啶-2-羧酸
在一个25mL的梨形烧瓶中,将上述制备的甲基6-(3,4-二氯苯基)-5-(2,2,2-三氟乙氧基)吡啶(326mg,858μmol,Eq:1.00)与四氢呋喃(5mL)合并,得到无色溶液。加入水(2.5ml),然后加入LiOH(41.1mg,1.72mmol,Eq:2),接下来将反应混合物于40℃搅拌2hr。将反应混合物倒入5mL sat.NH4Cl sol.和3mL 1N KHSO4 sol.中,并用EtOAc(2x30mL)萃取。合并有机层,用Na2SO4干燥,并真空浓缩,所得为322mg白色泡沫状标题酸;MS(ESI)366.4,368.4(M+H)+。
e)6-(3,4-二氯苯基)-N-[(1R,2R)-2-羟基环己基]-5-(2,2,2-三氟乙氧基)吡啶-2-甲酰胺
在一个25mL的梨形烧瓶中,将上述合成的6-(3,4-二氯苯基)-5-(2,2,2-三氟乙氧基)-吡啶甲酸(322mg,879μmol,Eq:1.00)在DMF(12mL)中溶解。添加TBTU(O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲四氟硼酸盐,424mg,1.32mmol,Eq:1.5,CAS登记号125700-67-6)和N,N-二异丙基乙基胺(568mg,768μl,4.4mmol,Eq:5),并于室温搅拌反应混合物10min,然后在不添加溶剂情况下加入(1R,2R)-2-氨基环己醇盐酸盐(160mg,1.06mmol,Eq:1.2,CAS登记号13374-31-7)。然后于室温下反应3h。粗混合物经H2O稀释,并且经CH2Cl2萃取。合并有机层,经Na2SO4干燥,并真空浓缩。采用快速层析法(碱性氧化铝,50g,10%至80%EtOAc的庚烷溶液)纯化,粗产物经EtOAc和庚烷沉淀得到为白色固体的标题酰胺;高分辨率MS(ESI)463.0798,465.0769(M+H)+;预期:463.0798,465.0768。
H(N′-(6-氯哒嗪基-3-基)-5-(4-氰基苯基)-N′-甲基-6-(2,2,2-三氟乙氧基)吡啶-3-碳酰肼)化合物的制备
按照WO 2014/180741中描述的步骤制备化合物H,步骤如下:
a)5-(4-氰基-苯基)-6-(2,2,2-三氟乙氧基)-烟酸甲酯
在一个50mL的4颈烧瓶中,将甲基5-溴-6-(2,2,2-三氟乙氧基)烟酸盐(1g,3.18mmol,Eq:1.00,CAS登记号1211589-51-3)和碳酸铯(3.11g,9.55mmol,Eq:3)与甲苯(25mL)和水(2.8mL)合并,得到一种无色溶液。反应混合物3倍脱气并用氩气净化;然后相继添加钯(II)醋酸盐(14.3mg,63.7μmol,Eq:0.02),钾(4-苯腈)三氟硼酸盐(732mg,3.5mmol,Eq:1.1,CAS登记号850623-36-8)和正丁基二-1-金刚烷基膦(68.5mg,191μmol,Eq:0.06,CAS登记号321921-71-5)。每次添加后重复脱气-净化循环。然后将反应混合物在120℃下加热5小时。冷却后,将反应混合物倒在50mL H2O上,并用AcOEt(2x50mL)萃取。有机层经H2O/盐水洗涤、合并,用Na2SO4干燥,并真空浓缩。采用快速层析法(硅胶,50g,50%至100%CH2Cl2的庚烷溶液)纯化,最终获得898mg为白色泡沫的标题化合物;MS(ESI)337.2(M+H)+。
b)5-(4-氰基-苯基)-6-(2,2,2-三氟乙氧基)-烟酸
在一个25mL的圆底烧瓶中,将上述制备的5-(4-氰基-苯基)-6-(2,2,2-三氟-乙氧基)-烟酸甲酯(0.891g,2.65mmol,Eq:1.00)与THF(7mL)和水(3.5mL)合并,得到一种淡黄色的两相体系。当TLC显示反应完成时,加入氢氧化锂(127mg,5.3mmol,Eq:2)并于40℃搅拌反应混合物3小时。整理:加入10mL H2O和7mL HCl 1N,混合物经AcOEt(2x50mL)萃取,合并有机层,用盐水洗涤,用Na2SO4干燥,并真空浓缩。以庚烷/乙酸乙酯9∶1进行调合,最终得到794mg为白色固体的期望标题产物;MS(ESI)321.2(M-H)-。
c)N′-(6-氯哒嗪基-3-基)-5-(4-氰基苯基)-N′-甲基-6-(2,2,2-三氟乙氧基)吡啶-3-碳酰肼
在一个5mL的圆底烧瓶中,将上述制备的5-(4-氰基-苯基)-6-(2,2,2-三氟-乙氧基)-烟酸(0.050g,155μmol,Eq:1.00)与THF(2mL)合并,得到无色溶液。添加TBTU(O-(苯并三唑-1-基)-N,N,N′,N′-四甲基脲四氟硼酸盐,74.7mg,233μmol,Eq:1.5,CAS登记号125700-67-6)和N,N-二异丙基乙基胺(100mg,135μL,776μmol,Eq:5)。反应混合物于室温(RT)搅拌10min,然后加入3-氯-6-(1-甲基吡嗪基)-哒嗪(29.5mg,186μmol,Eq:1.2,CAN76953-33-8),然后将反应混合物在RT条件下过夜。倒入25mL 1M HCl,用EtOAc(2x50mL)萃取,用1M NaOH洗涤,用Na2SO4干燥并于真空中蒸发所有溶剂,然后采用快速层析法(硅胶,10g,2%至10%MeOH的CH2Cl2溶液)并用庚烷/AcOEt结晶,最终产生28mg为白色固体的标题化合物;MS(ESI)463.1,465.3(M+H)+。
6-(4-氯苯基)-5-(2,2,2-三氟乙氧基)-吡啶-2-羧酸(3-异丙基-异噁唑-5-基甲基)-酰胺化合物J的制备
按照WO 2014/180741中所述的步骤制备化合物J,步骤如下:
标题化合物由6-(4-氯苯基)-5-(2,2,2-三氟乙氧基)-吡啶-2-羧酸和3-(1-m甲基乙基)-5-甲胺异恶唑盐酸盐(CAS登记号543713-30-0),按照WO 2012/032018中实例64所述的方法合成。LC-MS(UV峰面积/ESI)100.0%,454.4(M+H)+。
Cpd F(6-(4-氯苯基)-N-(嘧啶-5-基)-5-(2,2,2-三氟乙氧基)吡啶甲酰胺,比较化合物)的制备:
6-(4-氯苯基)-5-(2,2,2-三氟乙氧基)-吡啶-2-羧酸(按照WO 2012/032018实例AE所述制备)与DMF(30ml)在RT条件下合并,得到一种无色溶液。加入嘧啶-5-胺、TBTU和N-乙基二异丙胺。将反应混合物在RT下搅拌15h。将该反应混合物倒入150mLH2O中,并且用EtOAc(2x150mL)萃取。将合并的有机层用盐水洗涤,经MgSO4干燥并蒸发。通过快速层析法(硅胶,20g,0%至50%EtOAc的乙烷溶液)纯化粗物质。LC-MS(ESI)409.068(M+H)+。
比较其它化合物
Cpd C(1,1,1,3,3,3-六氟-2-{2-甲基-1-[5-甲基-2-(3-三氟甲基-苯基)-噁唑-4-基甲基]-1H-吲哚-5-基}-丙-2-醇,LXR激动剂)的合成按照WO 2005/105791中实例56所述进行。
Cpd D(4-{5-[(RS)-(3-溴-苯磺酰基)-((SR)-7-氯-1,2,3,4-四氢-环戊烯并[b]吲哚-2-基)-氟-甲基]-[1,3,4]噁二唑-2-基}-苯甲酸,部分LXR激动剂)按照WO 2005/092856中实例113所述进行。
Cpd E((R)-2-[(S)-苯磺酰基-氟-(5-甲基-[1,3,4]噁二唑-2-基)-甲基]-7-氯-1,2,3,4-四氢-环戊烯并[b]吲哚,部分LXR激动剂)按照WO 2005/092856中实例74(6)进行。
材料和方法
在体外实验中,冻干化合物于DMSO(Sigma)中重构并在同一溶剂中稀释成20mM、10mM、5mM、1mM和0mM的原液,储存于-20℃下。
在体内实验中,冻干的化合物悬浮在溶媒中(由Roche设计的一种特殊制剂:1.25%羟丙基甲基纤维素、0.10%多库酯钠盐、0.18%尼泊金丙酯钠、0.02%一水合柠檬酸,pH 6)。在冰面上进行3次简短超声以配制细微颗粒悬浮液。调整悬浮液中化合物浓度调整如下:Cpd C(LXR激动剂)为2mg/ml;和ABCA1诱导剂、Cpd A和Cpd G均为6mg/ml和20mg/ml两个浓度。化合物悬浮液长期储存于-20℃,且如果化合物将在一周内使用则置于4℃。施用前充分混合悬浮液,以确保施用均匀。
细胞培养
大鼠I型胶原蛋白、RPMI和ITS购自Corning。FBS购自GIBCO,无脂BSA购自Sigma-Aldrich。用于胆固醇外排测定的人ApoA1和3H-胆固醇分别购自Calbiochem和AmericanRadiolabeled Chemicals。
条件永生化人类足细胞由Moin Saleem馈赠。细胞接种于I型胶原蛋白包被的培养瓶中,并于补充有1X ITS的完全培养基(RPMI,10%FBS,1X青/链霉素)中在33℃、5%CO2条件下繁殖。为了分化,以2,500个细胞/cm2的密度,在不含ITS的完全培养基中接种细胞,并在37℃、5%CO2条件下培养15天。
细胞毒性
将足细胞接种于96孔平板(Greiner)中,并分化14天。然后用PBS洗涤细胞,并用含有或不含有溶媒和化合物的培养基(RPMI-0.2%BSA)在37℃、5%CO2条件下孵育18h。测试的化合物浓度为1μM、5μM、10μM和20μM。溶媒(DMSO)终浓度为0.1%。所有处理一式两份进行。遵循制造商的说明采用ApoTox-Glo Triplex Assay(Promega)进行细胞毒性测定。简言之,将细胞渗透(GF-AFC)和非细胞渗透(bis-AAF-R110)肽底物稀释并添加到所有孔中,然后将细胞在37℃、5%CO2条件下孵育1小时。用皂苷(2mg/ml)处理一组细胞,作为细胞毒性的阳性对照组。分别在400nm/505nm和485nm/520nm激发波长/发射波长下使用荧光酶标仪(SpectraMax i3)检测细胞活性和细胞毒性荧光信号。将从细胞毒性底物获得的RFU信号标准化至用同孔中活性底物获得的RFU信号,以消除每孔细胞数不同的影响。
胆固醇外排
在含2%FBS的RPMI培养基中用1μCi/ml的[3H]-胆固醇标记分化13天的人类足细胞,持续24h。然后用PBS洗涤细胞,并用补充有溶媒或化合物Cpd C(1μM)、Cpd A(1μM、5μM)和Cpd G(1μM、5μM、10μM)的平衡培养基(RPMI-0.2%无脂BSA)孵育18h。然后用PBS洗涤细胞,并用含有或不含有20μg/ml人ApoA1的平衡培养基在37℃,5%CO2条件下孵育18h。收集培养基,以12,000x g旋转5min然后用液体闪烁谱仪对200μl等分试样的放射性进行计数。用PBS洗涤细胞,用250μl 0.1%SDS、0.1M NaOH裂解,然后用液体闪烁谱仪对100μl等分试样的放射性进行测量。胆固醇外排是标记胆固醇从细胞转移到培养基的百分比(%),计算公式为:
外排(%)=100x{(cpm培养基)/[(cpm培养基)+(cpm裂解物)]}
ApoA1介导的胆固醇外排计算为存在或不存在ApoA1时的外排之差。所有处理一式两份进行。进行了3次以上的独立实验。
ABCA1的表达。
分化14天的足细胞在RPMI-0.2%FBS中饥饿18h,然后用新鲜制备的化合物稀释液在完全培养基中在37℃和5%CO2条件下处理18h。评估1μM、5μM和10μM的化合物浓度。然后用PBS洗涤细胞,并用补充有蛋白酶和磷酸酶抑制剂混合物(Roche)的1X细胞裂解缓冲液(Cell Signaling)裂解细胞。用BCA法测定总蛋白含量(Pierce,Thermoscientific)。采用蛋白质免疫印迹分析ABCA1的表达。
细胞分级
用化合物Cpd C(1μM)、Cpd A(5μM)和Cpd G(10μM)处理分化14天的足细胞18h,然后用冰冷PBS洗涤并刮下细胞。将细胞以1000x g离心5min,小心吸出上清,然后用补充有Roche蛋白酶抑制剂混合物的低渗缓冲液(15mM KCl、1.5mM MgCl2、10mM HEPES和1mM DTT)重悬所得沉淀。通过在玻璃搅拌器中起泡和两次冻融循环来保证进一步的细胞破碎。向细胞中加入终浓度227mM的蔗糖,在4℃下,以1000x g离心30min。然后将上清液转移到新管中,在4℃下以10000x g离心15分钟。收集含微粒体级分的沉淀,并将上清液转移到新的管中,在4℃下,以100,000x g离心1小时。收集沉淀的质膜级分,并将含非膜性胞质组分的上清液在Vivaspin 500过滤器柱中浓缩。通过蛋白质免疫印迹验证了每个级分中ABCA1的存在,以及膜(Na+/K+钠泵)和胞浆(MEK)上已知蛋白的存在。
蛋白质免疫印迹
裂解液或细胞级分与缓冲样品在还原条件下于55℃孵育10分钟。通过含4-20%凝胶(Biorad)的SDSPAGE将裂解液中总量为的蛋白和三分之一体积所收集的细胞级分制备物分离,然后将蛋白转印到PVDF膜上。用5%牛奶封闭膜,并用蛋白特异性抗体在4℃下印迹18h。使用了以下抗体:小鼠抗ABCA1抗体(Abcam;1∶1,000),兔抗GAPDH抗体(Millipore;1∶10,000),兔抗MEK和抗Na+/K+ATPase(Cell Signaling;1∶1,000)。用PBS-T洗涤后,将膜与1∶10,000的偶联了HRP的抗小鼠和抗兔特异性抗体在5%牛奶中一起孵育(Promega)。洗涤膜,并使用Western Bright ECL底物(Advansta)显影信号。
体内实验
研究批准
用于测试小鼠中化合物的研究方案已由迈阿密大学IACUC批准。迈阿密大学(UM)具有在美国国立卫生研究(NIH)院实验动物福利办公室备案的动物福利保证书(A-3224-01,于2014年11月24日生效)。此外,UM在美国农业动植物卫生检验局注册,于2014年12月生效,注册号为58-R-007。截至2013年10月22日,实验动物护理评估和认证协会(AAALACInternational)的认证委员会已延续了UM的全面认证。
阿霉素-诱导的肾脏损伤
6周龄雌性Balb/c小鼠购自Jackson Labs,并在实验开始前于我们的机构中饲养了两周。
首先,我们进行了预实验,以探索要使用的化合物的最佳剂量,并确定是否需要调整其他实验变量。在该实验中,30只小鼠接受了单剂量的阿霉素(Sigma-Aldrich,12mg/Kg,通过尾静脉注射),然后随机分为6组,每组5只。另外5只小鼠通过相同的途径注射0.9%NaCl,并被用作无肾脏损伤的基线组。自ADR注射后24小时开始,通过口服管饲每天一次给予溶媒或不同剂量的化合物,持续35天。测试的化合物的剂量如下:LXR激动剂(Cpd C,10mg/Kg);ABCA1诱导剂Cpd A和Cpd G(30mg/Kg和100mg/Kg)。每周完成一次体重测量和点尿收集。ADR注射后35天处死动物(图1)。
重复第二个实验,以确认在第一个实验中,所用Cpd A和Cpd G的剂量实现了肾功能的改善。简言之,用12mg/Kg的ADR经尾静脉注射30只8周龄的雌性Balb/c小鼠,然后将小鼠随机分为5组,每组6只动物。从ADR注射后的一天开始,动物通过口服管饲每天一次被给予溶媒或化合物,持续28天。测试了以下剂量的化合物:Cpd C,10mg/Kg/日;Cpd A,30mg/Kg/日和Cpd G,30mg/Kg/日和100mg/Kg/日。将接受了尾静脉生理盐水注射以及溶媒处理的一组5只动物作为健康基线组。每周完成一次体重测量和点尿收集。ADR注射后28天处死动物(图2)。
Alport小鼠模型
129Col4a3tm1/Dec/J小鼠购自Jackson Labs,然后进行了繁殖以产生Col4a3 KO小鼠。用下述引物对小鼠进行基因分型和选择:F(TGCTCTCTCAAATGCACCAG),R(CCAGGCTTAAAGGGAAATCC)和Rm(GCTATCAGGACATAGCGTTGG),PCR反应条件为94℃5分钟,然后30个循环为95℃30秒,60℃15秒和72℃30秒,以及72℃1分钟。将129Col4A3-KO小鼠分成两组,每组5只小鼠(雄性和雌性)。从4周龄时,小鼠开始通过口服管饲每天一次接受溶媒或Cpd G(100mg/Kg),持续4周。每周进行一次体重测量和点尿收集。在8周龄处理结束时,处死动物。还进行了一项后期研究,以评估Col4A3-KO小鼠发病时的处理是否能延长小鼠的存活情况。在这项研究中,从6周龄开始用Cpd G(100mg/Kg/日)每日口服管饲处理小鼠,并评估了存活情况。
DKD小鼠模型
B6.BKSdb/db和B6.BKSdb/+小鼠购自Jackson laboratory。从14周龄时,小鼠开始通过口服管饲每天一次接受溶媒或ABCA1诱导剂Cpd A(30mg/Kg),持续4周。每周进行体重测量和尿液收集。在18周龄时处死小鼠,并以如下所述采血和处理组织。
小鼠的表型分析
在基线处和处死时收集所有小鼠的点尿样品。使用白蛋白ELISA试剂盒(Bethyllaboratories)和肌酐测定比色法(Stanbio)分别测定尿白蛋白和肌酐。计算白蛋白尿并表示为μg白蛋白除以mg肌酐。对于糖尿病小鼠模型,每两周测量一次体重和血糖。
在处死时,用肝素管收集血液,并用等渗盐溶液通过左心室灌注小鼠。仔细剥离肾脏皮层并进一步制成切片以进行下述分析:测定足细胞数量、脂滴染色、电子显微镜(EM)、肾脂质含量测定、PAS&HE染色用以病理评估。
足细胞数的测定
将肾皮质切片包埋入OCT中,以进一步分析免疫荧光染色和脂滴。具体地,为了测定每个肾小球横截面的足细胞数,使用切片并用WT1抗体(1∶200,Santa Cruz)染色的厚度为4μm的组织切片来测定,并延长GOLD DAPI封固剂的使用。使用具有40x湿式物镜的LeicaSP5倒置显微镜通过共焦显微镜获取图像。每只小鼠定量20张肾小球切片。
脂滴染色用滤过的油红色O-异丙醇溶液(Electron Microscopy Science,PA)水稀释(6∶4)。将4μm肾脏切片与100μl新鲜制备的油红O溶液(ORO)孵育15分钟,并用苏木精哈里斯游离汞(VWR,PA)复染以检测脂质沉积。使用光学显微镜(Olympus BX 41,东京,日本)评估肾小球染色。
电子显微术。将肾皮质切片置于4%低聚甲醛、1%戊二醛的0.1M磷酸盐缓冲液(pH7.4)中以进行透射电子显微术。定量每1μm的肾小球基底膜的足突。
肾脂质种类测定。将肾皮质切片速冻并用于脂质提取和胆固醇含量测定。在冰上的玻璃匀浆器中将组织在2mM磷酸钾缓冲液中均质化。用1ml己烷:异丙醇(3∶2)对100μl匀浆物(约5-10mg组织)中的脂质进行连续两次30分钟提取。然后将含有脂质的溶剂在氮气气氛下干燥。然后使用异丙醇重构脂质:使用Amplexred胆固醇测定试剂盒(Invitrogen)根据制造商的方案对NP-40(9∶1)和胆固醇含量进行定量。根据制造商的说明(Cayman),使用比色试剂盒测定脂质提取物中的甘油三酸酯。总胆固醇和胆固醇酯使用酶促荧光法测定。对于总胆固醇,将肾脂质提取物在测定缓冲液(100mM磷酸钾,50mM NaCl,5mM胆酸,0.1%Triton X-10,pH 7.4)中稀释,并与补充有终浓度为1U/ml胆固醇氧化酶、1U/ml胆固醇酯酶、1U/ml辣根过氧化物酶和75μM Amplex Red的测定缓冲液一起孵育。将反应在不透明的黑色96孔板(Greiner)中于37℃孵育30分钟,并使用530nm激发波长和580nm发射波长在酶标仪(Spectramax i3X,Molecular Devices)中测量荧光。
使用Mizoguchi等人(Mizoguchi,2004)描述的直接方法测定胆固醇酯。简言之,将150μl的FC分解试剂(在上述测定缓冲液中为45U/ml牛过氧化氢酶和1U/ml胆固醇氧化酶)添加到总胆固醇最高为1mM的25μl样品中。使游离胆固醇在37℃下分解过夜,然后添加75μl的4X胆固醇酯检测试剂(1U/ml胆固醇氧化酶、4U/ml胆固醇酯酶、24U/ml辣根过氧化物酶、300μM Amplex Red)。将反应在37℃下孵育30分钟,并按上述总胆固醇测量方法测量荧光。将1mM的胆固醇和5μM的胆固醇油酸酯标准品作为内部对照,以验证测定的敏感性和特异性。
病理学评价。肾皮质切片经石蜡包埋并切成4μm厚,用于高碘酸-Schiff(PAS)和HE。根据半定量分析(0-5级)或肾小球与肾小球系膜扩张的百分比(%)采用双盲模式对系膜扩张进行评分。
统计学
统计学所有值均用平均值和SD表示。使用Prism GraphPad 7软件进行统计分析。如果使用了1种以上的化合物剂量,并且组呈正态数据分布,则使用单因素ANOVA结果。如果观察到差异,则使用Dunnett检验将对照组(溶媒)的平均值与每组的平均值进行比较。进行Tukey检验以进行多重比较。
使用双尾t检验比较了体内研究的溶媒组和Cpd处理组。在方差不相等的情况下使用Welch校正。当不能确定各组呈正态分布时,也可使用Mann-Whitney检验比较各组。P值<0.05%为具有统计学意义。
结果
化合物细胞毒性
我们通过细胞毒性测定来确定Cpd在培养的人足细胞中可安全使用的浓度范围。
所有化合物均可在多至10μM浓度下使用而无细胞毒性特征。然而,我们决定使用浓度不超过5μM的Cpds A和C,因为这两种化合物在20μM时具有显著的毒性(图3)。
ABCA1的表达和胆固醇外排
我们进行了体外实验,以选择出在足细胞中能更好地诱导ABCA1功能表达的化合物,用于进一步的动物实验。因此,我们研究了化合物对ABCA1蛋白表达、ABCA1在质膜中的定位和ApoA1介导的胆固醇外排的影响。
采用蛋白质免疫印迹法检测化合物诱导的ABCA1表达。所有LXR激动剂、Cpd C、CpdE和Cpd D在低至1uM的低剂量时均可显著增加足细胞中ABCA1的表达。在测试的三种ABCA1诱导剂(Cpd A、Cpd F和Cpd G)中,只有Cpd A和Cpd G增加了ABCA1的表达,但其在10uM时,没有LXR激动剂显著(图4a)。
为了解决所见ABCA1表达的增加是否与更多的功能蛋白产生有关,我们对用1μMCpd C、5μM Cpd A和10μM Cpd G处理后的足细胞进行了细胞分级。我们首先验证了ABCA1的表达随药物浓度的增加而增加(图4b),然后通过蛋白质免疫印迹检查了ABCA1在所得各级分中的定位。所得级分还经过了质膜上已知蛋白和胞质级分、Na+/K+ATP酶和MEK印迹,以验证细胞分级成功(图4c-e)。所用三种化合物的剂量促进了ABCA1在质膜上的定位(图4c),并且正如预期的,在非膜胞质级分中未发现ABCA1。ABCA1诱导剂Cpd A和Cpd G处理后的细胞微粒体室中ABCA1较少(图4d),表明这些化合物在促进该蛋白在质膜上的定位中比LXR激动剂更效。此外,我们使用ApoA1作为胆固醇载体进行胆固醇外排测定。本测定测量了ABCA1在胆固醇外排方面的功能,因为ABCA1与ApoA1特异性地相互作用,可将胆固醇从细胞转移到新生HDL颗粒。1μM CpdC(LXR激动剂)、5μM Cpd A和10μM Cpd G(图4d至图4e)可显著增加ApoA1介导的外排。
基于上述体外试验,我们选择了ABCA1诱导剂Cpd A和Cpd G,并以LXR激动剂Cpd C作为参比,在肾损伤动物模型中进行测试。
ABCA1诱导剂防止实验性FSGS
肾损伤的ADR模型是一种药物诱导的蛋白尿肾病模型,目前仍是最广泛使用的局灶节段性肾小球硬化(FSGS)实验模型。对选自体外实验的化合物进行剂量范围调查实验。
ADR注射诱导严重的一过性蛋白尿和体重下降。每周检查一次白蛋白尿和体重。LXR激动剂处理组中未观察到显著差异(Cpd C,图5a)然而,接受30mg/Kg的Cpd A组和接受100mg/Kg的Cpd G组的蛋白尿减少(图5b和图5e),并且接受30mg/Kg的Cpd G组程度更轻(图5d)。同样地,注射ADR的动物体重下降10-20%,用30mg/Kg的Cpd A和100mg/Kg的Cpd G处理的动物中阻止这种体重减轻(图5g和图5j),但LXR激动剂不能(图5f)。
在第二个独立的体内试验中,我们利用了更多数量的老鼠并选择了之前的实验中发现的有利剂量的Cpd A和Cpd G,即30mg/Kg的Cpd A和100mg/Kg的Cpd G。与之前实验相似,两种ABCA1诱导剂减少了蛋白尿和体重下降(图6b)。
由于发现化合物G是一种效果最好的化合物,并且肾脏疾病的ADR模型不存在肾功能受损,因此我们在用该化合物处理的动物中进行了附加定量组织学研究。一项对肾脏皮质的盲性病理研究显示,接受100mg/Kg/日Cpd G的动物的总体和节段性肾小球硬化、足细胞肥大和增生、肾小管微囊肿和间质炎症均有所减轻(图7)。这些数据共同表明,化合物G在减少阿霉素引起的FSGS标志方面非常有效,并且比LXR激动剂更有效。
当施用预期会影响胆固醇代谢的化合物时,我们测量了实验动物血液中的胆固醇和甘油三酸酯水平。两项临床参数均为发现显著差异(表1和表2)。
表1.ADR注射后35天,用溶媒、LXR激动剂(Cpd C)和ABCA1诱导剂(Cpd A和Cpd G)处理的动物血液中胆固醇和甘油三酸酯。
表2.ADR注射后28天,用溶媒、LXR激动剂(Cpd C)和ABCA1诱导剂(Cpd A和Cpd G)处理的动物的血液胆固醇和甘油三酸酯。
已记录肾损伤情况下肾组织中的脂质沉积。我们进行了油红O(ORO)染色,以确定注射ADR的动物中是否存在脂质沉积以及Cpd G是否可以减小这种影响。在ADR注射小鼠的肾脏中发现了脂滴的显著沉积,该现象在用Cpd G处理的动物中显著减少(图8)。事实上,受溶媒的ADR注射小鼠肾皮质中脂质沉积显著,相反,Cpd G完全防止了肾小球脂质对ADR应答产生的沉积,与年龄匹配的正常对照组小鼠相比,未发现肾皮质中存在可检测到的脂质积聚。
为了确定在肾组织中积累的脂质种类,我们提取了肾皮质的脂质,并分析了它们的甘油三酸酯、总胆固醇和胆固醇酯。我们未发现注射ADR或生理盐水的动物肾脏中甘油三酯和总胆固醇的含量有差异。但是,我们发现ADR注射小鼠中酯化胆固醇的含量明显更高,而Cpd G处理显著降低了酯化胆固醇的含量(图9a-c)。白蛋白尿的严重程度与肾组织中检测到的胆固醇酯含量有很强的相关性(图9d),但与分析的其他脂质种类无关(图9e和图9f)。对ADR注射小鼠的Cpd G处理防止胆固醇酯的积累,并且在不愿受到任何理论束缚的情况下,据信该化合物可通过上调ABCA1促进肾小球胆固醇的清除。
接下来我们通过血清学研究化合物C、化合物A和化合物G的毒性。更具体地,我们测定了所有处理动物的红细胞压积、血红蛋白、白细胞计数和肝转氨酶ALT和AST,以确定这些化合物是否与肝脏毒性和血液异常有关。在实验小鼠中未发现此类毒性的明显迹象(表3)
表3:用化合物C、化合物A或化合物G处理35天后的动物,与溶媒对照组相比,在WBC、血红蛋白、红细胞压积以及ALT和AST转氨酶水平均中未显示异常。数据代表了每个参数的平均值和标准差。
在整个实验过程中,以最佳剂量的Cpd G处理的动物比接受ADR的动物具有更好的体征。这在治疗的第3周和第4周尤为明显(图10)。
Cpd G可防止进展性肾病(Alport综合征)小鼠模型的肾衰竭
未经治疗的CoL4a3 KO小鼠在4至8周龄时出现严重的白蛋白尿以及高BUN和血清肌酐水平。这些小鼠在8周龄之前达到ESRD,并且在该时间点后无法存活。
为了研究Cpd G对该Alport综合征模型的肾保护效果,从4周龄开始我们用100mg/Kg Cpd G或溶媒处理CoL4a3 KO小鼠4周。与仅接受溶媒处理的动物相比,经100mg/Kg CpdG处理的动物表现出向ESRD发展的延迟,蛋白尿、BUN和血清肌酐显著减少(见图11)。经CpdG处理的动物也比接受溶媒的动物体重下降更少。
肾脏切片的组织学分析显示Cpd G处理的Col4a3 KO小鼠的系膜扩张显著小于溶媒处理的Col4a3 KO小鼠。另一项单独的研究是为了研究在患有肾功能衰竭的小鼠中用CpdG处理是否会改善生存情况。事实上,即使在患有相对晚期CKD的6周小鼠身上开始使用CpdG处理,用Cpd G处理的Col4a3 KO小鼠肾功能的改善与死亡率降低相关,这导致寿命延长了近15%。
最后,8周龄Co14a3 Ko小鼠肾皮质切片显示显著的脂质沉积(油红O染色增加),该现象在接受Cpd G的小鼠中有所减少(见图13)。与ADR模型中的先前结果一致,Cpd G处理显著减少了胆固醇酯显著高于WT同窝小鼠的Col4a3 KO小鼠肾脏中的胆固醇酯。
CpdA对糖尿病肾病小鼠模型有部分保护作用
增加的ABCA1可以逆转足细胞损伤和DKD
我们旨在验证ABCA1作为肥胖糖尿病db/db小鼠模型中DKD的治疗靶点。与溶媒处理的db/db小鼠相比,用ABCA1的药物诱导剂处理的Db/db小鼠在处理两周(16周)后蛋白尿减少,在处理四周(18周)后蛋白尿甚至进一步减少(图12A)。与db/db小鼠相比,ABCA1诱导剂(化合物A)处理组的血尿素氮(BUN)明显改善(图12B),这与胆固醇酯的显著减少有关(图12C-D)。用于各种组织学评估的肾皮质切片显示,ABCA1诱导剂处理的db/db小鼠得到了改善:通过定量WT1阳性细胞确定足细胞数量(图12E-F),使用PAS染色切片确定系膜扩张(图12G-H),使用TEM图像确定足细胞足突消退(图12I-J)。
Claims (15)
1.化合物在制备用于治疗Alport综合征的药物上的用途,其中所述化合物为选自由以下项组成的组的ABCA1诱导剂化合物:
5-(3,4-二氯-苯基)-N-((1R,2R)-2-羟基-环己基)-6-(2,2,2-三氟-乙氧基)-烟酰胺,
6-(3,4-二氯苯基)-N-[(1R,2R)-2-羟基环己基]-5-(2,2,2-三氟乙氧基)吡啶-2-甲酰胺,
和其药用盐。
2.根据权利要求1所述的化合物的用途,所述化合物为5-(3,4-二氯-苯基)-N-((1R,2R)-2-羟基-环己基)-6-(2,2,2-三氟-乙氧基)-烟酰胺。
3.根据权利要求1所述的化合物的用途,所述化合物为6-(3,4-二氯苯基)-N-[(1R,2R)-2-羟基环己基]-5-(2,2,2-三氟乙氧基)吡啶-2-甲酰胺。
4.根据权利要求1至3中任一项所述的化合物的用途,所述化合物经配制用于口服施用。
5.根据权利要求1至3中任一项所述的化合物的用途,所述化合物经配制用于局部施用。
6.根据权利要求1至3中任一项所述的化合物的用途,所述化合物经配制用于鼻内、眼内、静脉内、肌内、皮下、鞘内或经皮施用。
7.根据权利要求1至3中任一项所述的化合物的用途,所述化合物经配制用于玻璃体内施用。
8.根据权利要求1至3中任一项所述的化合物的用途,其中每日剂量为20至800mg/日。
9.根据权利要求1至3中任一项所述的化合物的用途,其中所述每日剂量为200mg/日。
10.根据权利要求1至3中任一项所述的化合物的用途,其中给药方案为每日一次、每日两次、每日三次、每三日一次、每周一次、每两周一次或每月一次。
11.根据权利要求1至3中任一项所述的化合物的用途,其中负荷剂量方案为前7天、前14天或前30天的剂量加倍。
12.根据权利要求1至3中任一项所述的化合物的用途,用于制备与选自由以下项组成的组中的化合物同时地、依序地或分别地使用的药物:血管紧张素转换酶(ACE)抑制剂药物;RAS阻滞剂;血管紧张素受体阻滞剂(ARB);蛋白激酶C(PKC)抑制剂;AGE依赖性通路抑制剂;抗炎剂;GAG;吡哆胺;内皮素拮抗剂、COX-2抑制剂、PPAR-γ拮抗剂、氨磷汀、环磷酰胺、硫代硫酸钠、曲尼司特、环糊精及其衍生物、维生素D衍生物、抗高血糖试剂和抗高胆固醇试剂。
13.根据权利要求1至3中任一项所述的化合物的用途,用于制备与卡托普利同时地、依序地或分别地使用的药物。
14.根据权利要求1至3中任一项所述的化合物的用途,用于制备与治疗有效量的血管紧张素转换酶抑制剂或血管紧张素受体阻滞剂同时地、依序地或分别地使用的药物。
15.根据权利要求1至3中任一项所述的化合物的用途,其中所述药物包括如权利要求1至3所定义的化合物和药用的载体和/或佐剂。
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JP7478133B2 (ja) | 2024-05-02 |
CN117736141A (zh) | 2024-03-22 |
EP3826679A1 (en) | 2021-06-02 |
US20200085810A1 (en) | 2020-03-19 |
TW202019486A (zh) | 2020-06-01 |
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