CN109718239A - 用于治疗低磷血性疾病的fgfr抑制剂 - Google Patents
用于治疗低磷血性疾病的fgfr抑制剂 Download PDFInfo
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Abstract
本发明一般涉及3‑(2,6‑二氯‑3,5‑二甲氧基‑苯基)‑1‑{6‑[4‑(4‑乙基‑哌嗪‑1‑基)‑苯基氨基]‑嘧啶‑4‑基}‑1‑甲基‑尿素或其药学上可接受盐或溶剂合物或者含3‑(2,6‑二氯‑3,5‑二甲氧基‑苯基)‑1‑{6‑[4‑(4‑乙基‑哌嗪‑1‑基)‑苯基氨基]‑嘧啶‑4‑基}‑1‑甲基‑尿素或其药学上可接受盐或溶剂合物的药物组合物,用于治疗X连锁低磷血症性佝偻病(XLH)、常染色体显性遗传性低磷血症性佝偻病(ADHR)、常染色体隐性遗传性低磷血症性佝偻病(ARHR)、肿瘤源性骨软化症、肾移植后低磷血症、表皮痣综合征、骨骼系统发育不良或多发性骨纤维营养不良。
Description
技术领域
本发明一般涉及3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐或溶剂合物或者含3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐或溶剂合物的药物组合物,其用于治疗成纤维细胞生长因子受体介导的疾病。
发明背景
成纤维细胞生长因子(FGF)家族和其信号转导受体与多种生物活性(增殖、生存、凋亡、分化、运动)相关,所述活性控制从蠕虫到人类的生物体生长和维持的关键过程(发育、血管生成和代谢)。已鉴定22种不同FGF,都共有保守的120-氨基酸核心结构域,序列同一性为15-65%。FGF23是磷酸盐体内平衡的关键、骨来源调节物,其在肾中的功能是调节维生素D生物合成和磷酸盐的肾吸收。在肾近端小管上皮细胞中,FGF23信号转导控制维生素D代谢酶CYP27B1和CYP24A1的表达,引起生物合成减少和活性维生素D代谢物1,25-二羟维生素D3(1,25[OH]2D3)的周转提高。另外,FGF23削弱肾近端小管细胞刷状缘膜中钠-磷酸盐共转运蛋白NPT2A和NPT2C的表达,其调节尿磷酸盐的再吸收。
FGF23水平过高或功能增强导致血磷酸盐过少以及1,25(OH)2D3(维生素D)生物合成受损,并且与数种遗传性低磷酸盐血症相关,其中骨骼异常是骨矿化受损的结果,包括X连锁低磷血症性佝偻病(XLH)、常染色体显性遗传性低磷血症性佝偻病(ADHR)和常染色体隐性遗传性低磷血症性佝偻病(ARHR)。另外,很少情况下鉴定出肿瘤的FGF23分泌导致血磷酸盐过少,引起肿瘤源性骨软化症(TIO)。还常在肾移植术后患者中观察到FGF23水平升高导致严重血磷酸盐过少。FGF23在若干其它低磷酸盐血症性综合征如表皮痣综合征、骨骼系统发育不良(osteoglophonic dysplasia)和多发性骨纤维营养不良中起作用,所述综合征与FGF23水平增加相关。XLH和其它FGF23介导的低磷酸盐血症如ADHR和ARHR通常在幼儿期有身材矮小和腿弯曲畸形的临床表现。
这些疾病的现有治疗方法主要限于膳食维生素D和磷酸盐补充。尽管治疗改善患者的生长和佝偻病,矫正通常有限且导致青春期后高度受损。根据疾病严重度,但由于FGF23信号转导的持续性-构成连续反作用力-给予高剂量磷酸盐和维生素D通常是XLH及其它FGF23相关低磷酸盐血症的药物治疗所需的,其需要密切监测和剂量调整以规避毒性风险如腹痛和腹泻或继发性甲状旁腺机能亢进、血钙过多和异位性钙化。
因此,需要可靠和有效药物用于治疗上述毁容疾病,并且通过阻断FGFR信号转导来直接靶向病理FGF23信号转导可提供相较现有治疗标准的有利治疗方法。
发明内容
目前意外发现式I所示化合物3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素(如WO2006/000420的实施例145所述)在临床上特别活跃且能用于治疗其它成纤维细胞生长因子受体介导的疾病,所述化合物是高度选择性FGFR抑制剂,也称为BGJ389。
第一方面,本发明因而提供3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐、N-氧化物或溶剂合物,用于治疗X连锁低磷血症性佝偻病(XLH)、常染色体显性遗传性低磷血症性佝偻病(ADHR)、常染色体隐性遗传性低磷血症性佝偻病(ARHR)、肿瘤源性骨软化症、肾移植后低磷血症、表皮痣综合征、骨骼系统发育不良或多发性骨纤维营养不良。特别地,所述化合物、其药学上可接受盐或溶剂合物能用于治疗X连锁低磷血症性佝偻病(XLH)、常染色体显性遗传性低磷血症性佝偻病(ADHR)、常染色体隐性遗传性低磷血症性佝偻病(ARHR)或肿瘤源性骨软化症、肾移植后低磷血症。
优选地,向患者给予一个剂量以上的3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐或溶剂合物。
化合物3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐、N-氧化物或溶剂合物如上所定义使用时,治疗应优选持续至少8周,可选有中断。2个连续化合物剂量之间的时间可以大于24小时,可选48小时。
式I的化合物能与另一FGFR抑制剂、磷酸盐、钙、骨桥蛋白(OPN)、甲状旁腺素或其类似物(PTH)、和/或维生素D或维生素D类似物组合,优选与磷酸盐、钙和/或维生素D或维生素D类似物,特别是维生素D或维生素D类似物组合进一步用于治疗。
第二方面,本发明提供含3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐、N-氧化物或溶剂合物的药物组合物,所述组合物如上所述使用。
本发明的另一方面是3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐、N-氧化物或溶剂合物,用于使皮质骨体积或厚度相较于对照或者治疗开始前的皮质骨体积或厚度而增加。
本发明的另一方面是3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐、N-氧化物或溶剂合物,用于增加患者体重,显示FGF23活性相较对照提高。
本发明的另外一方面是3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐、N-氧化物或溶剂合物,用于抑制骨中的FGF23表达或抑制骨中的FGF23活性。
附图简要说明
图1FGFR抑制剂治疗诱导Hyp小鼠中的1,25(OH)2D3生物合成并缓解低血钙症和低磷酸盐血症。显示FGFR体内抑制7小时后,肾FGF23靶基因Cyp27b1(A)和Cyp24a1(B)的调节。数据显示为相比野生型载剂对照组的相对水平(相对表达为100)。(C)如A和B所述治疗的野生型和Hyp小鼠的血清1,25(OH)2D3水平通过放射受体分析法测定。用单一口服剂量BGJ398(50mg/kg)或载剂治疗的野生型和Hyp小鼠中,给药后24小时的钙(E)和磷酸盐(F)水平。从血清测定磷酸盐和钙水平。数据表示为均值与SEM(n≥6)。数据通过非配对学生t检验比较;*p<0.05;**p<0.01;***p<0.001;n.s.:不显著。
图2FGFR抑制剂治疗调节Dmp1缺失小鼠中的肾FGF23靶基因表达并缓解低血钙症和低磷酸盐血症。FGFR体内抑制后,肾FGF23靶基因Cyp27b1(A)和Cyp24a1(B)的调节。数据显示为相比野生型载剂对照组的相对水平(相对表达为100)并表示为均值与标准误差(SEM)(n≥6)。野生型和Dmp1缺失小鼠中,药理学FGFR抑制对血清钙(C)和磷酸盐(D)水平的效果。数据表示为均值与SEM(n≥6)。数据通过非配对学生t检验比较;*p<0.05;**p<0.01;***p<0.001;n.s.:不显著。
图3显示FGFR依赖性信号转导调节骨中的FGF23表达。用BGJ398治疗7小时的野生型和Hyp小鼠中,FGF23骨mRNA(A)和血清(B)水平。
图4显示FGFR抑制剂治疗引起钙和磷酸盐血清水平持续增加。给予式I化合物后48小时,从野生型和Hyp小鼠的血清中测定钙(A)和磷酸盐(B)水平。(C)7和24小时治疗后肾中的化合物浓度。
图5长期FGFR抑制提高Hyp小鼠的体重和尾长发育并恢复矿物离子体内平衡。野生型或Hyp小鼠用FGFR抑制剂BGJ398(50mg/kg)或载剂每周治疗3次(3qw),持续56天,监测体重(A)和尾长(C)发育。治疗过程中的总体重(B)和尾长增加(D)。最终给药后24小时从血清测定8周治疗结束时钙(E)和磷酸盐的水平。数据表示为均值与SEM(n≥6)。数据通过非配对学生t检验比较;*p<0.05;**p<0.01;***p<0.001;n.s.:不显著。
图6用BGJ398长期FGFR抑制后的FGF23、甲状旁腺素(PTH)和1,25(OH)2D3血清水平。野生型或Hyp小鼠用FGFR抑制剂BGJ398(50mg/kg)或载剂每周治疗3次,持续56天,并在最终给药后24小时从血清测定FGF23(A)、PTH(B)和1,25(OH)2D3(C)水平。数据显示为均值与SEM(n≥4)。数据通过非配对学生t检验比较;*p<0.05;**p<0.01;***p<0.001;n.s.:不显著。
图7长期FGFR抑制提高Hyp小鼠的长骨生长。用FGFR抑制剂BGJ398(50mg/kg)或载剂每周治疗3次、持续56天的野生型或Hyp小鼠中股骨(A)和胫骨(B)的射线照片。定量股骨(C)和胫骨(D)长度。数据显示为均值与SEM(n≥6)。数据通过非配对学生t检验比较;*p<0.05;**p<0.01;***p<0.001;n.s.:不显著。
图8长期FGFR抑制改善Hyp小鼠股骨的皮质完整性。(A)用FGFR抑制剂BGJ398(50mg/kg)或载剂每周治疗3次、持续56天的野生型或Hyp小鼠中股骨皮质(亚生长板区域)的微CT扫描。定量相对皮质骨体积(B)和平均皮质厚度(C)。数据显示为均值与SEM(n≥6)。数据通过非配对学生t检验比较;*p<0.05;**p<0.01;***p<0.001;n.s.:不显著。
图9显示用FGFR抑制剂BGJ398(50mg/kg)或载剂每周治疗3次、持续56天的野生型或Hyp小鼠中胫骨切片的戈德纳染色(A)。矿化组织用白色箭头指示,未矿化类骨质用黑色箭头指示,在用BGJ398(50mg/kg)或载剂每周治疗3次、持续56天的野生型或Hyp小鼠前胫距中通过组织形态测定术测定(B)类骨质表面/骨表面和类骨质宽度(C)。数据显示为均值与SEM(n≥6)。数据通过非配对学生t检验比较;*p<0.05;**p<0.01;***p<0.001。
发明详述
已知成纤维细胞生长因子23(FGF23)。认为其是有广泛生物活性的成纤维细胞生长因子家族一员。所述蛋白序列和/或所述蛋白编码序列可获自本领域已知的公开可用数据库。人FGF23也在本领域称为ADHR;HYPF;HPDR2;PHPTC。FGF23是数种低磷酸盐血症的致病因子。意外观察到用FGFR抑制剂3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素(BGJ398)药理学抑制FGFR会抵消病理FGF23信号转导,从而指示治疗FGF23相关低磷酸盐血症的潜在新型治疗方法。发现3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐、N-氧化物或溶剂合物用于治疗X连锁低磷血症性佝偻病(XLH)、常染色体显性遗传性低磷血症性佝偻病(ADHR)、常染色体隐性遗传性低磷血症性佝偻病(ARHR)、肿瘤源性骨软化症、肾移植后低磷血症、表皮痣综合征、骨骼系统发育不良或多发性骨纤维营养不良时可以非常有效。所述化合物能特别有效用于治疗X连锁低磷血症性佝偻病(XLH)、常染色体显性遗传性低磷血症性佝偻病(ADHR)或常染色体隐性遗传性低磷血症性佝偻病(ARHR)、肾移植后低磷血症,尤其是X连锁低磷血症性佝偻病(XLH)和常染色体显性遗传性低磷血症性佝偻病(ADHR)或常染色体隐性遗传性低磷血症性佝偻病(ARHR)。
在一个实施方式中,本文所用术语“治疗(“treat”、“treating”或“treatment”)”任何疾病或病症指缓解疾病或病症(即减慢或阻滞或减少疾病发展或其至少一种临床症状的发展)。在另一个实施方式中,“治疗(“treat”、“treating”或“treatment”)”指减轻或缓解至少一种身体参数,包括患者可能无法识别的那些。在另一个实施方式中,“治疗(“treat”、“treating”或“treatment”)”指调节疾病或病症,或是身体上(如可识别症状的稳定)或是生理上(如身体参数的稳定)或两者。在另一个实施方式中,“治疗(“treat”、“treating”或“treatment”)”指防止或延迟疾病或病症发生或发展或进展。
术语“药学上可接受盐”指根据本发明使用时保留化合物的生物有效性和特性的盐,且其通常不是生物学或其他方面不合需要的。药学上可接受酸加成盐能用无机酸和有机酸形成,如乙酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、溴化物/氢溴化物、碳酸氢盐/碳酸盐、硫酸氢盐/硫酸盐、樟脑磺酸盐、氯化物/氢氯化物、氯茶碱盐(chlortheophyllonate)、柠檬酸盐,乙二磺酸盐、富马酸盐、葡庚糖酸盐、葡糖酸盐、葡糖醛酸盐、油酸盐、草酸盐、棕榈酸盐、双羟萘酸盐、磷酸盐/磷酸氢盐/磷酸二氢盐、丙酸盐、硬脂酸盐、琥珀酸盐、磺基水杨酸盐、酒石酸盐、甲苯磺酸盐、三氟乙酸盐等。可由其获得盐的无机酸包括例如盐酸、氢溴酸、硫酸、硝酸、磷酸等。在一个实施方式中,所述药学上可接受盐是化合物3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素的单磷酸盐(或磷酸盐),其可任选采用无水晶形。在特定实施方式中,所述化合物的盐是WO2011/071821公开的任何盐或形式。在一个实施方式中,3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素采用游离碱形式。
术语“溶剂合物”指化合物与一个或多个溶剂分子的分子复合物。这种溶剂分子是常用于药物领域的那些,其已知对化合物无害,如水、乙醇等。
化合物3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素的N-氧化物之一具有下列式II
BGJ398给药后7小时,单一有效剂量的BGJ398已引起野生型和Hyp小鼠的1,25(OH)2D3血清水平强劲增加。另外,钙和磷酸盐水平也增加。这些结果表明药理学抑制FGFR足以抵消哺乳动物中的异常FGF23信号转导。发现单剂量FGFR抑制剂已在抵消FGF23活性和平衡体内钙及磷酸盐水平方面产生影响。此外,长期用BGJ398治疗使得Hyp小鼠中的钙和磷酸盐水平完全正常。因此,在一个优选实施方式中,向需要的患者给予多于一个治疗有效剂量的BGJ398或其药学上可接受盐、N-氧化物或溶剂合物。术语“治疗有效剂量”的化合物指会引起对象生物学或医学响应的BGJ398量,例如降低或抑制激酶活性、或缓解症状、减轻病症、减慢或延缓疾病进展、或防止疾病等。所述对象可以是任何哺乳动物,包括人。就约50-70kg对象而言,治疗有效剂量可以是约1-250mg BGJ398,或约1-150mg例如125mg剂量、或约0.5-100mg、或约1-50mg、或约1-25mg、或约1-10mg的BGJ398。所述化合物的治疗有效剂量取决于对象种类、体重、年龄和个体情况、病症或疾病或者所治疗病症或疾病的严重度,所述化合物单独或采用药物组合物形式或联合其它活性成分,如下文所述。
本发明的另一方面是3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐、N-氧化物或溶剂合物,用于使皮质骨体积或厚度相较对照或者治疗开始前的皮质骨体积或厚度而增加。所实施的实验清楚显示对象用BGJ398治疗时,皮质骨体积从病理值增加到与正常值无法区分。另外,皮质厚度显著增加。
观察到给予3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素引起患者体重增加,所示患者显示FGF23活性相较对照提高。“对照”指没有各自疾病的个体、数个对象或群体中FGF23活性或表达值。
广义上,本发明的一个实施方式是3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐、N-氧化物或溶剂合物,用于抑制骨中FGF23表达或抑制骨中FGF23活性。“表达”指基因转录和翻译时产生的核酸或氨基酸。例如,转录活性能通过任何合适方法评价,包括例如检测从FGF23基因转录的mRNA量或从转录自所述基因的mRNA逆转录生成的cDNA量或所述基因编码的多肽或蛋白量。或者,基因拷贝数、转录或翻译中的任意一种能用已知技术测定。例如,扩增方法如PCR可能有用。通过影响骨中FGF23表达或活性,可调节其结构和生长,这特别有效用于以不规则或无效生长呈现自身并导致异常的疾病,所述异常例如但不限于佝偻病。
为减少全身FGFR抑制的可能副作用发生,可间歇性给予剂量以使不需要的副效应最小,所述副效应可能对对象有害。能连续给予剂量而无中断,或首先起始于数个剂量以在需要其的患者中达到稳态浓度,然后改变剂量间的时间。或者,所述给药可在第一剂量后立即调整。2个连续化合物剂量之间的时间可大于24小时,可选48小时或甚至一周。在一个具体实施方式中,重复给予所述剂量,可选再次为2个连续剂量间1、2或3天,或仅在复发后。
在一个优选实施方式中,化合物3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素能与另一FGFR抑制剂、磷酸盐、钙、骨桥蛋白(OPN)、甲状旁腺素或其类似物(PTH)、和/或维生素D或维生素D类似物联用于治疗,优选联合磷酸盐、钙和/或维生素D或维生素D类似物,特别是维生素D或维生素D类似物。BGJ389可有利地组合使用以带来累加或甚至协同效果,并且还降低用更高剂量BGJ389的需求且连续限制副作用风险。
磷酸盐能以任何形式使用,其口服或胃肠外服用时增加无机磷(P)的血液水平,这可例如通过紫外线法在血清中测量,使用诸如来自英国朗道实验诊断有限公司(RANDOXLaboratories LTD)的试剂盒、和临床化学分析仪如HITACHI 717分析仪(罗氏诊断公司(Roche Diagnostics))。钙也能采用任何形式,其最终在服用时引起总钙的血液水平上升,这可例如通过紫外线法在血清中测量,使用诸如来自英国朗道实验诊断有限公司的试剂盒和临床化学分析仪如HITACHI 717分析仪。骨桥蛋白(OPN)称为分泌型磷蛋白1、骨唾液蛋白I或早期T淋巴细胞活化1,其为已知的。认为其是参与骨重建的胞外结构蛋白。人骨桥蛋白在本领域称为SPP1。已知甲状旁腺素(PTH)或甲状旁腺激素。认为其是参与调节血液中钙水平的激素。PTH类似物是至少部分保留PTH活性且结构类似完整PTH的分子,其仅仅更短或经修饰或有连接PTH主体结构的额外取代基。维生素D是负责钙稳态且对健康骨表型重要的已知激素。其类似物是模拟维生素D化学结构并引起药理学作用的结构相似化合物。维生素D类似物的一个示例是钙泊三醇。
3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐、N-氧化物或溶剂合物在药物组合物中配制,所述组合物进而能用于上述任何治疗。所述药物组合物通常会包括3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐、N-氧化物或溶剂合物以及一种或多种药学上可接受赋形剂。所述药物组合物中化合物的量优选为治疗有效量。可选地,向本发明所述药物组合物加入另一FGFR抑制剂、磷酸盐、钙、骨桥蛋白(OPN)、甲状旁腺素或其类似物(PTH)、和/或维生素D或维生素D类似物,优选联合磷酸盐、钙和/或维生素D或维生素D类似物,特别是维生素D或维生素D类似物。所述药物组合物可配制用于特定给药途径如口服给药、胃肠外给药、和局部给药等。另外,本发明的药物组合物可以固体形式(包括但不限于胶囊剂、片剂、丸剂、颗粒剂、粉剂或栓剂)、或液体形式(包括但不限于溶液、悬液或乳液)构成。所述药物组合物能接受常规制药操作如压缩、压片、过滤、冻干、灭菌等。赋形剂可以是任何常规惰性稀释剂、润滑剂、缓冲剂、粘合剂、崩解剂、甜味剂、芳香剂,以及佐剂如防腐剂、稳定剂、增湿剂、乳化剂、溶剂、分散介质、涂层剂、表面活性剂、抗氧化剂、防腐剂(如抗菌剂、杀真菌剂)、等渗剂、吸收延迟剂、盐、防腐剂、药物稳定剂、染料等及其组合。
实施例1
FGFR抑制剂治疗诱导Hyp小鼠中的1,25(OH)2D3生物合成并缓解低血钙症和低磷酸盐血症。野生型C57BL/6和Hyp(B6.Cg-PhexHyp/J)小鼠获自杰克逊实验室(JacksonLaboratory)。Dmp1缺失小鼠由Feng等(J.Dent.Res.2003;82:776-780.)生成。将所有小鼠关在标准实验室条件下的笼子中。对小鼠喂以标准啮齿动物饲料,可自由饮水。
野生型或Hyp小鼠接受单口服剂量的游离碱形式FGFR抑制剂BGJ398(50mg/kg)或载剂,并在给予所述化合物后7小时加以研究。BGJ398或单独载剂(PEG-300/葡萄糖5%,2:1混合)通过口头强喂给予。在单剂量给药情况中使用5-7周龄小鼠。通过吸入异氟醚来麻醉小鼠并从腔静脉采血。以放血法处死小鼠,获得肾和胫骨及股骨。还测定7h时肾中的BGJ398浓度。
对肾进行取样,分离总RNA。对于从小鼠胫骨及股骨分离RNA,切下骨骺并通过4℃离心移出骨髓。用Precellyis 24珠均质器匀化组织且用TRIzol试剂提取RNA。随后通过氯仿提取、异丙醇沉淀和RNeasy迷你试剂盒纯化RNA。对于肾RNA,用转子-定子式匀浆器在1.5ml RTL缓冲液(凯杰公司(Qiagen))中匀化约60mg组织,并用RNeasy迷你试剂盒纯化RNA。通过0.5-2μg RNA和MultiScribe MuLV逆转录酶合成具有随机六聚体引物的cDNA。
基因表达通过定量实时PCR(qPCR)分析。基于TaqMan探针的基因表达测定用于小鼠Cyp27b1(Mm01165919)、Cyp24a1(Mm00487244)和Gapdh(4352339E)的表达分析。用于检测小鼠Fgf23的引物和FAM/TAMRA标记探针(Microsynth)序列是5’-TTTGGATCGCTTCACTTCAG(正向),5’-GTGATGCTTCTGCGACAAGT(反向)和5’-CGCCAGTGGACGCTGGAGAA(探针)。定量实时PCR在iQ5实时PCR检测系统中进行,使用qPCR核心试剂盒(用于探针测定)和40或80ng RNA当量的各样品。数据根据Gapdh表达进行标准化。
股骨和胫骨的射线照片用高分辨率辐射成像系统(Faxitron MX-20)离体拍摄。用Scanco vivaCT 40系统(像素大小6μm;高分辨率)离体进行μCT测量。对于松质骨和皮质骨分析,采用固定200阈值测定50张切片的矿化骨部分。应用高斯滤波器以移除噪音(σ=0.7;支持=1)。
用含促凝剂的离心管从全血分离血清。通过VetScan诊断分析系统将100μl血清用于测定磷酸盐和钙水平。用放射受体分析试剂盒测定1,25(OH)2D3的血清浓度。通过检测完整FGF23的ELISA(凯诺斯(Kainos))分析FGF23血清水平。
FGF23部分通过转录调节肾中的1,25(OH)2D3代谢酶CYP27B1和CYP24A1来发挥其低磷酸盐血症性功能。因此,在用单剂量BGJ398治疗Hyp小鼠和野生型同窝鼠后,监测肾Cyp27b1和Cyp24a1表达。尽管Hyp小鼠中出现FGF23水平提高,但Hyp小鼠的Cyp27b1和Cyp24a1表达以及1,25(OH)2D3血清水平与野生型小鼠相比,没有显著差异(图1A、B和C),这可能是由于适应过程且与先前报道相符。在野生型和Hyp小鼠中,用BGJ398治疗7小时使得Cyp27b1水平增加且几乎完全丧失Cyp24a1表达(图1A和B)。因此,FGF23靶基因的这种去调节使得BGJ398给药后7小时的野生型和Hyp小鼠中1,25(OH)2D3血清水平都有强劲增加(图1C)。
给药后24小时,单剂量BGJ398治疗在野生型和Hyp小鼠中都诱导血清钙和磷酸盐水平提高,因而缓解对照Hyp小鼠中观察到的严重低血钙症和低磷酸盐血症。关于钙,经BGJ398治疗的Hyp小鼠血清水平与载剂治疗的野生型小鼠无法区分(图1D),而用FGFR抑制剂治疗的Hyp小鼠中血清磷酸盐浓度仍显著低于野生型小鼠血清水平(图1E)。图1A和B中的数据显示为相比野生型对照组的相对水平(相对表达为100)并表示为均值与标准误差(SEM)(n≥6)。
如所述,图1中描述FGFR体内抑制后,肾FGF23靶基因Cyp27b1(A)和Cyp24a1(B)的调节。同样,如A和B所述治疗的野生型和Hyp小鼠的(C)血清1,25(OH)2D3水平通过放射受体分析法测定。另外,显示用单口服剂量BGJ398(50mg/kg)或载剂治疗的野生型和Hyp小鼠中,给药后24小时的钙(图1E)和(图1F)磷酸盐水平。这共同显示FGFR抑制剂治疗诱导Hyp小鼠的1,25(OH)2D3生物合成并缓解低血钙症和低磷酸盐血症。所述结果进一步表明FGFR的药理学抑制足以抵消Hyp小鼠中的异常FGF23信号转导。
实施例2
FGFR抑制剂治疗调节Dmp1缺失小鼠中的肾FGF23靶基因表达并缓解低血钙症和低磷酸盐血症。图2显示FGFR体内抑制后,肾FGF23靶基因Cyp27b1(图2A)和Cyp24a1(图2B)的调节。除了在Phex缺陷型Hyp模型中的发现以外,在Dmp1缺失小鼠中观察到肾Cyp27b1和Cyp24a1表达的类似调节,Dmp1缺失小鼠是另一FGF23相关低磷酸盐血症模型(图2A和B)。野生型或Dmp1缺失小鼠接受单口服剂量的FGFR抑制剂BGJ398(50mg/kg)或载剂,并在给予所述化合物后7小时再次加以研究。如之前,对肾进行取样,分离总RNA且通过qPCR分析基因表达。表达值根据Gapdh mRNA拷贝进行标准化。A和B中的数据显示为相比野生型载剂对照组的相对水平并表示为均值与标准误差(SEM)(n≥6)。
对于钙和磷酸盐水平分析,小鼠接受单口服剂量的FGFR抑制剂BGJ398(50mg/kg)或载剂并在给药后24小时研究。从血清测定磷酸盐和钙水平。对于Hyp小鼠,药理学FGFR抑制引起Dmp1缺失小鼠中血清钙和磷酸盐水平增加(分别为图2C和D)。图2的数据显示为均值与标准误差(SEM)(n≥6)。数据通过非配对学生t检验比较;*p<0.05;**p<0.01;***p<0.001;n.s.:不显著。
实施例3
图3显示FGFR依赖性信号转导调节骨中的FGF23表达。除了减轻2种FGF23相关低磷血症性佝偻病小鼠模型中的矿物离子缺乏,还注意到FGFR抑制剂治疗对经BGJ398治疗的Hyp小鼠中FGF23水平的抑制效果。小鼠接受单口服剂量的FGFR抑制剂BGJ398(50mg/kg)或载剂,并在给药后7小时加以研究。测定用BGJ398治疗的野生型和Hyp小鼠中,FGF23骨mRNA(图3A)和血清(图3B)水平。BGJ398给药后7小时,Hyp和野生型小鼠骨中的FGF23表达几乎消失(图2A)。FGF23转录抑制导致野生型小鼠的血清FGF23水平无法检测,而Hyp小鼠的病理性高FGF23水平降低约50%(图3B)。图中mRNA表达显示为相比野生型载剂对照组的相对水平(相对水平为100)并表示为均值与标准误差(SEM)(n≥7)。FGF23mRNA表达值根据GapdhmRNA拷贝进行标准化。数据通过非配对学生t检验比较;*p<0.05;**p<0.01;***p<0.001。
实施例4
图4清楚显示FGFR抑制剂治疗引起钙和磷酸盐血清水平持续增加。与实施例1类似,野生型或Hyp小鼠接受单口服剂量的FGFR抑制剂BGJ398或载剂,并在给予所述化合物后48小时加以研究。从血清中测定钙(图4A)和磷酸盐(图4B)水平。数据显示为均值与标准误差(SEM)(n≥3)。数据通过非配对学生t检验比较;*p<0.05;**p<0.01;***p<0.001;n.s.:不显著。(C)给药后7小时和24小时的肾中BGJ398浓度。值表示为均值与标准误差(SEM)(n≥5)。
实施例5
长期FGFR抑制提高Hyp小鼠的体重和尾长发育并恢复矿物离子体内平衡。进行长期治疗研究以监测Hyp小鼠模型中佝偻病样骨表型的潜在改善。实施8周进程的治疗。由于钙和磷酸盐水平持续上升-延伸超过BGJ398从肾中清除(图4)-小鼠用BGJ398(50mg/kg体重)或载剂每周治疗3次(3qw),持续56天,与上述类似分析。图5显示所监测的体重(图5A)和尾长(图5C)发育。图5还显示治疗过程中的总体重(图5B)和尾长增加(图5D)。最终给药后24小时从血清测定8周治疗结束时钙(图5E)和磷酸盐(图5F)的水平并示于图5。数据表示为均值与SEM(n≥6)。数据通过非配对学生t检验比较;*p<0.05;**p<0.01;***p<0.001;n.s.:不显著。
相较野生型同窝鼠,Hyp小鼠显示5周龄,即治疗开始时的体重下降。治疗过程中,Hyp小鼠中的药理学FGFR抑制使得体重比载剂对照组增加更多(图5A)。总体上,经BGJ398治疗的Hyp小鼠的总体重增加与经载剂治疗的野生型小鼠类似(图5B)。尾部更短是Hyp小鼠低磷血症性佝偻病的显著特征,反映骨形成受损。因此,我们监测8周治疗中的尾长发育并发现经BGJ398治疗的Hyp小鼠显示尾长增加远高于对照Hyp小鼠(图5C)。此外,用FGFR抑制剂治疗的Hyp小鼠的尾长增加还显著高于经载剂治疗的野生型同窝鼠(图5D)。为检测连续FGFR抑制对Hyp小鼠中磷酸盐和钙体内平衡的效果,分析8周研究结束时的血清钙和磷酸盐浓度。发现与单剂量FGFR抑制剂给药相反(图1D和E),用BGJ398长期治疗引起Hyp小鼠中钙和磷酸盐水平完全正常化(图5E和F)。
实施例6
图6显示用BGJ398长期抑制FGFR后FGF23、甲状旁腺素(PTH)和1,25(OH)2D3的血清水平。野生型或Hyp小鼠再次用FGFR抑制剂BGJ398(50mg/kg)或载剂每周治疗3次,持续56天,并在最终给药后24小时从血清测定FGF23(图6A)、甲状旁腺素(PTH)(图6B)和1,25(OH)2D3(图6C)水平。用含促凝剂的离心管(Sarstedt)从全血分离血清,从而测定PTH值。将20μl血清用于测定PTH水平,其使用小鼠PTH ELISA(Immutopics)。数据通过非配对学生t检验比较;*p<0.05;**p<0.01;***p<0.001;n.s.:不显著。
尽管FGFR抑制对FGF23表达有短暂抑制效果(见图3),但用BGJ398长期治疗引起Hyp小鼠中FGF23血清浓度进一步增加(图6A),这伴随着PTH水平正常化(图6B),而1,25(OH)2D3在治疗组间没有显著差异(图6C)。
实施例7
如图7所示,长期FGFR抑制提高Hyp小鼠的长骨生长。总之,上面这些结果阐明药理学FGFR抑制在异常FGF23信号转导背景下的有益效果并指示Hyp小鼠的骨形成缺陷有潜在减轻。因此,通过放射线照相术分析长期(8周)FGFR抑制对股骨和胫骨纵向生长的影响,发现经BGJ398治疗的Hyp小鼠显示股骨(图7A和C)和胫骨(图7B和D)相较载剂治疗的对照组显著加长。FGFR抑制确实部分减轻股骨和胫骨生长板区域加宽,这通常在佝偻病中观察到(图7A和B)。图7中:用FGFR抑制剂BGJ398(50mg/kg)或载剂每周治疗3次、持续56天的野生型或Hyp小鼠中股骨(图7A)和胫骨(图7B)的射线照片。定量股骨(图7C)和胫骨((图7D)长度。数据显示为均值与SEM(n≥6)。数据通过非配对学生t检验比较;*p<0.05;**p<0.01;***p<0.001;n.s.:不显著。
实施例8
长期FGFR抑制改善Hyp小鼠股骨的皮质完整性。为更详细确定FGFR抑制剂治疗对骨结构的效果,对用FGFR抑制剂BGJ398(50mg/kg)或载剂每周治疗3次、持续56天的野生型或Hyp小鼠中股骨皮质(亚生长板区域)进行微计算机x线断层成像术(μCT)分析(图8A)。定量更多相对皮质骨体积(图8B)和测定平均皮质厚度(图8C)。此分析显示Hyp小鼠皮质骨区域的矿化受损,通过Hyp股骨皮质结构内的缝隙和孔洞表现出来(图8A,由箭头指示)。相较野生型小鼠,经载剂治疗的Hyp小鼠显示皮质骨区域的相对骨体积减少(图8B)且平均皮质厚度降低(图8C)。相反,经BGJ398治疗的Hyp小鼠的皮质呈现完整(图8A),相对皮质骨体积与野生型小鼠无法区分(图8B)且皮质厚度相较载剂治疗的Hyp小鼠显著增加(图8C)。
因此,分析揭示FGFR抑制对Hyp小鼠中骨的纵向生长和结构完整性产生有益效果。
实施例9
用BGJ398长期治疗恢复Hyp小鼠的生长板组织。还发现在胫骨组织切片中,BGJ398治疗对Hyp小鼠的生长板组织有缓解效果(图9A)。图9显示用FGFR抑制剂BGJ398(50mg/kg)或载剂每周治疗3次、持续56天的野生型或Hyp小鼠中胫骨切片的戈德纳染色(图9A)。矿化组织用白色箭头指示,用深灰色呈现未矿化类骨质(用黑色箭头指示)。通过浅灰色染色在切片中央部分显示生长板结构(图9B)。在用BGJ398(50mg/kg)或载剂每周治疗3次、持续56天的野生型或Hyp小鼠前胫距中通过组织形态测定术测定类骨质表面/骨表面和类骨质宽度(图9C)。数据显示为均值与SEM(n≥6)。数据通过非配对学生t检验比较;*p<0.05;**p<0.01;***p<0.001。在经载剂治疗的Hyp小鼠中,软骨细胞的柱状构造和定向生长被扰乱,与野生型小鼠的高度有序结构相反。另外,对照Hyp小鼠中的矿化受损,如未矿化类骨质丰度所示。然而,在经BGJ398治疗的Hyp小鼠中,观察到生长板区域的显著重建(图9A,左图)和软骨细胞柱状堆叠的再形成以及增生带的高度增加(图9B,右图)。另外,注意到毗邻生长板的骨骺骨区域矿化提高以及干骺端亚生长板区域形成初级松质,这在经载剂治疗的Hyp小鼠中几乎没有。同样,组织形态分析揭示FGFR抑制后Hyp小鼠的OS/BS比增加减弱(图9B)且骨骺、干骺端和皮质骨隔室内类骨质宽度大幅下降(图9C)。
总之,数据表明FGFR的药理学抑制足以抑制异常FGF23信号转导并缓解XLH的低磷血症性佝偻病表型和潜在其它FGF23相关低磷酸盐血症如ARHR。特别地,连续给药FGFR抑制剂BGJ398后Hyp小鼠中磷酸盐和钙水平完全正常化以及佝偻病类似骨中生长板区域重建是前景广阔的,因为这构成低磷血症性佝偻病表型潜在逆转的前提。
Claims (10)
1.3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐、N-氧化物或溶剂合物用于治疗X连锁低磷血症性佝偻病(XLH)、常染色体显性遗传性低磷血症性佝偻病(ADHR)、常染色体隐性遗传性低磷血症性佝偻病(ARHR)、肿瘤源性骨软化症、肾移植后低磷血症、表皮痣综合征、骨骼系统发育不良或多发性骨纤维营养不良的应用。
2.3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐、N-氧化物或溶剂合物用于治疗X连锁低磷血症性佝偻病(XLH)、常染色体显性遗传性低磷血症性佝偻病(ADHR)或常染色体隐性遗传性低磷血症性佝偻病(ARHR)的应用。
3.3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐或溶剂合物用于使皮质骨体积或厚度相较对照或者治疗开始前的皮质骨体积或厚度而增加的应用。
4.3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐、N-氧化物或溶剂合物用于抑制骨中的FGF23表达或抑制骨中的FGF23活性的应用。
5.如权利要求1-4中任一项所述的3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素的应用,所述3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素处于单磷酸盐形式。
6.如权利要求1-4中任一项所述的3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素的应用,所述3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素处于游离碱形式。
7.如前述权利要求中任一项所述的3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素的应用,其特征在于,所述剂量是1-50mg。
8.如权利要求7所述的3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素的应用,其特征在于,所述待治疗疾病是X连锁低磷血症性佝偻病(XLH)、常染色体显性遗传性低磷血症性佝偻病(ADHR)或常染色体隐性遗传性低磷血症性佝偻病(ARHR)。
9.如权利要求1-8中任一项所述的3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐、N-氧化物或溶剂合物的应用,所述3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐、N-氧化物或溶剂合物与另一FGFR抑制剂、磷酸盐、钙、骨桥蛋白(OPN)、甲状旁腺素或其类似物(PTH)、和/或维生素D或维生素D类似物联合,优选与磷酸盐、钙和/或维生素D或维生素D类似物,特别是维生素D或维生素D类似物联合。
10.一种药物组合物,所述组合物包括如权利要求1-8中任一项中定义应用的3-(2,6-二氯-3,5-二甲氧基-苯基)-1-{6-[4-(4-乙基-哌嗪-1-基)-苯基氨基]-嘧啶-4-基}-1-甲基-尿素或其药学上可接受盐、N-氧化物或溶剂合物。
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