CN112469696A - 供在由衰老细胞引起或介导的状况的临床管理中使用和用于治疗癌症的作为Bcl家族拮抗剂的酰基磺胺 - Google Patents
供在由衰老细胞引起或介导的状况的临床管理中使用和用于治疗癌症的作为Bcl家族拮抗剂的酰基磺胺 Download PDFInfo
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Abstract
此发明的芳基磺胺化合物具有有力且细胞类型特异性的Bcl抑制性活性。在这类中选择的化合物促进衰老细胞中的凋亡,而且正在开发用于治疗衰老相关状况。在这类中选择的化合物促进癌细胞中的凋亡,而且可以开发成为化疗剂。
Description
优先权申请
此申请要求在2018年6月13日提交的第62/684,681号美国临时专利申请的优先权。据此通过援引将优先权申请完整收入本文用于所有目的。
发明领域
下文公开和要求保护的技术一般涉及衰老细胞和它们在年龄相关状况中的作用的领域。特别地,此公开提供抑制Bcl蛋白质活性的新的小分子化合物。
发明背景
衰老细胞特征在于细胞不再具有复制能力,但是保留在起源组织中,引发衰老相关分泌表型(SASP)。此公开的一项前提是许多年龄相关状况是由衰老细胞介导的,而且在临床上可以使用自该状况处或周围的组织选择性去除该细胞来治疗此类状况。
美国专利10,130,628(Laberge等人)记载了使用MDM2抑制剂,Bcl抑制剂,和Akt抑制剂治疗认为是至少部分由衰老细胞介导的某些年龄相关状况。US 20170266211 A1(David等人)记载了特定Bcl抑制剂用于治疗年龄相关状况的用途。美国专利8,691,184,9,096,625,和9,403,856(Wang等人)记载了小分子文库中的Bcl抑制剂。
涉及衰老细胞在人疾病中的作用的其它公开文本包括授权前出版物US 2017/0056421 A1(Zhou等人),WO 2016/185481(Yeda Inst.),US 2017/0216286 A1(Kirkland等人),和US 2017/0281649 A1(David);和Furhmann-Stroissnigg等人(Nat Commun.2017Sep4;8(1):422),Blagosklonny(Cancer Biol Ther.2013Dec;14(12):1092-7),和Zhu等人(Aging Cell.2015Aug;14(4):644-58)的论文。
发明概述
下面的公开概述用于选择性消除衰老细胞的一种策略,并提供有效化合物,药学组合物,开发策略,和治疗方案,并描述许多随之而来的益处。
已经开发了Bcl抑制剂的一个新家族。这个家族中的一些Bcl抑制剂是特别有效的衰老消解剂。在体外或在体内使衰老细胞与此公开的化合物和组合物接触选择性调控或消除此类细胞。该抑制剂可用于施用于具有年龄相关状况的受试者中的靶组织,由此选择性消除该组织中或周围的衰老细胞并缓解该状况的一种或多种症状或体征。或者/另外,可以作为化疗剂配制和销售自该家族选择的化合物。
在下面的描述中,在附图中,和在所附权利要求中列出该发明。
附图简述
图1显示用于化学合成依照此发明的例示性化合物的通用合成方案。
图2A,2B,和2C分别显示一种骨关节炎动物模型中衰老细胞标志物p16,IL-6,和MMP13的表达。可通过抑制MDM2的衰老消解剂Nutlin-3A来改善衰老表型。可以选择依照此发明的Bcl抑制剂作为衰老消解剂用于相同目的。
图3A显示一种有效的衰老消解剂恢复骨关节炎模型中接受治疗的小鼠的对称负重。图3B,3C,和3D是显示这些小鼠中的关节的组织病理学的图像。用该药剂治疗有助于防止或逆转对蛋白聚糖层的破坏。
图4A和4B显示当玻璃体内施用衰老消解剂时小鼠氧诱导的视网膜病(OIR)模型中新血管形成和血管闭塞二者的逆转。图4C和4D取自用于糖尿病性视网膜病的链唑霉素(STZ)模型。玻璃体内施用衰老消解剂削弱STZ诱导的血管渗漏。
图5显示在用于吸烟(CS)诱导的COPD(慢性阻塞性肺部疾病)的一种小鼠模型中去除衰老细胞有助于恢复氧饱和(SPO2)。
图6显示取自用于动脉粥样硬化的一种小鼠模型的数据,其中对缺乏LDL受体的近交小鼠喂食高脂肪饮食。右边小图显示主动脉中的斑块的染色。中间小图定量显示通过用衰老消解剂治疗减小了斑块覆盖的主动脉的表面积。
发明详述
衰老细胞特征在于不再具有复制能力,但是保留在起源组织中,引发衰老相关分泌表型(SASP)的细胞。此公开的一项前提是许多年龄相关状况是由衰老细胞介导的,而且自该状况处或周围的组织选择性去除该细胞可以在临床上用于此类状况的治疗。
下文描述和要求保护的技术代表第一次描述一类新的Bcl抑制剂,出于治疗年龄相关状况的目的,其可用于自靶组织选择性消除衰老细胞。
抑制Bcl蛋白质活性
Bcl蛋白质家族(TC#1.A.21)包括分享Bcl-2同源(BH)域的在进化上保守的蛋白质。Bcl蛋白质因它们在线粒体处上或下调凋亡(程序性细胞死亡的一种形式)的能力而最为著名。提供下面的解释以帮助使用者理解此公开的化合物的一些科学基础。这些概念不是实施发明所需要的,它们也不以超出明确叙述或要求的任何方式限制本文描述的化合物和方法的用途。
在此公开的语境中,特别感兴趣的Bcl蛋白质是那些下调凋亡的。抗凋亡Bcl蛋白质含有BH1和BH2域,它们中的一些含有另外的N端BH4域(Bcl-2,Bcl-x(L)和Bcl-w(Bcl-2L2),抑制这些蛋白质提高细胞对凋亡的易感性或速率。如此,此类蛋白质的抑制剂可用于帮助消除其中表达该蛋白质的细胞。
在2000年代中期,Abbott Laboratories开发了Bcl-2,Bcl-xL和Bcl-w的一种新颖抑制剂,称作ABT-737(Navitoclax)。这种化合物是靶向这些Bcl-2家族蛋白质,但非A1或Mcl-1的一组BH3模拟小分子抑制剂(SMI)的一部分。鉴于它更高的对Bcl-2,Bcl-xL和Bcl-w的亲和力,ABT-737优于先前的BCL-2抑制剂。体外研究显示来自具有B细胞恶性的患者的原代细胞对ABT-737敏感。在人患者中,ABT-737有效针对一些类型的癌细胞,但是遭受剂量限制性血小板减少症。
现在已经发现本文描述的化合物贴合入Bcl蛋白质的活性位点以提供强Bcl抑制和/或促进靶细胞凋亡。这些化合物可开发成靶向衰老细胞和癌细胞的高度有力且特异性的药物,如下面的各节中描述的。
模型化合物
发明的许多化合物具有落在下文显示的式的范围内的结构。
其中:
X1是卤化物,优选-Cl;
X2是-COOH;
X3是-SO2CF3;-SO2CH3;或-NO2;
X5是-F或-H;
R1是-CH(CH3)2;
R2是-H或-CH3任一,优选-CH3;
R3和R4独立是-H或-CH3任一,优选均是-H;
n1是1至3,优选2;且
式中的任何可能构件附带以下前提,如果X3是-SO2CF3,那么R6中的羟基基团必须是磷酸化的。在与任何上述选项组合时,根据使用者的选项,X2的-COOH基团可以是磷酸化的,与羟基基团一样或代替羟基。
“磷酸化”形式的化合物是其中一个或多个-OH或-COOH基团已经用或是-OPO3H2或是-CnPO3H2(其中n是1至4)的磷酸根基团取代,使得可以在体内去除磷酸根基团(例如通过酶解)的化合物。非磷酸化或去磷酸化形式没有此类基团。
除非明确说明或另有要求,在没有立体化学的情况下描绘的化合物包括所有立体异构体的外消旋混合物,和在对映异构体上纯的制备物,任一对映异构体作为备选。任何式I化合物典型但非必须具有下文式I中描绘的立体化学:
其还可以如下描绘:
其中每个R3独立是-H或-CH3任一。
此发明的许多化合物具有落在下文显示的式II的范围内的结构。
其还可以如下描绘:
其中:
X1是-Cl;
X2是-COOH;
X3是-SO2CF3;-SO2CH3;或-NO2;
X5是-F或-H;
R1是-CH(CH3)2;
R2是-CH3;
R3和R4均是-H;
n1是2;且
R7是-H,-P(O)(OH)2,或-(CnH2n)P(O)(OH)2(其中n是1至4或1至8);
前提是,如果X3是-SO2CF3,那么R7是-P(O)(OH)2或-(CnH2n)P(O)(OH)2。
这分开和一起包括如显示的R7的酸形式和其盐形式(诸如当R7是-P(O)(ONa)2或-(CnH2n)P(O)(ONa)2时)二者。
作为物质的组合物或特定背景中的用途,可以任选使用或请求保护此公开和/或每种结构式中列出的每种化学种类,前提是它没有在美国专利8,691,184,9,096,625,和9,403,856(Wang等人)任一中明确和确切描绘或描述。可以任选使用或请求保护此公开和/或每种结构式中列出的每种化学种类,前提是它没有在US 20170266211 A1(David等人)中明确和确切描绘或描述。
可能符合依照此公开的制备和/或用途的例示性化合物在表1A中显示。
表1A
(R)-5-(4-氯苯基)-1-异丙基-2-甲基-4-(3-(4-(4-((4-((1-(苯基硫)-4-(4-(膦酰氧基)哌啶-1-基)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-1-异丙基-2-甲基-4-(3-(4-(4-((3-(甲基磺酰基)-4-((1-(苯基硫)-4-(4-(膦酰氧基)哌啶-1-基)丁烷-2-基)氨基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-氟-5-(4-(4-((3-(甲基磺酰基)-4-((1-(苯基硫)-4-(4-(膦酰氧基)哌啶-1-基)丁烷-2-基)氨基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-1-异丙基-2-甲基-4-(3-(4-(4-((3-硝基-4-((1-(苯基硫)-4-(4-(膦酰氧基)哌啶-1-基)丁烷-2-基)氨基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-氟-5-(4-(4-((3-硝基-4-((1-(苯基硫)-4-(4-(膦酰氧基)哌啶-1-基)丁烷-2-基)氨基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-1-异丙基-2-甲基-4-(3-(4-(4-((4-((1-(苯基硫)-4-(4-((膦酰氧基)甲基)哌啶-1-基)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-氟-5-(4-(4-((4-((1-(苯基硫)-4-(4-((膦酰氧基)甲基)哌啶-1-基)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-1-异丙基-2-甲基-4-(3-(4-(4-((3-(甲基磺酰基)-4-((1-(苯基硫)-4-(4-((膦酰氧基)甲基)哌啶-1-基)丁烷-2-基)氨基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-氟-5-(4-(4-((3-(甲基磺酰基)-4-((1-(苯基硫)-4-(4-((膦酰氧基)甲基)哌啶-1-基)丁烷-2-基)氨基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-1-异丙基-2-甲基-4-(3-(4-(4-((3-硝基-4-((1-(苯基硫)-4-(4-((膦酰氧基)甲基)哌啶-1-基)丁烷-2-基)氨基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-氟-5-(4-(4-((3-硝基-4-((1-(苯基硫)-4-(4-((膦酰氧基)甲基)哌啶-1-基)丁烷-2-基)氨基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-1-异丙基-2-甲基-4-(3-(4-(4-((4-((1-(苯基硫)-4-(膦酰氧基)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-1-异丙基-2-甲基-4-(3-(4-(4-((3-(甲基磺酰基)-4-((1-(苯基硫)-4-(膦酰氧基)丁烷-2-基)氨基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-氟-5-(4-(4-((3-(甲基磺酰基)-4-((1-(苯基硫)-4-(膦酰氧基)丁烷-2-基)氨基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-1-异丙基-2-甲基-4-(3-(4-(4-((3-硝基-4-((1-(苯基硫)-4-(膦酰氧基)丁烷-2-基)氨基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-氟-5-(4-(4-((3-硝基-4-((1-(苯基硫)-4-(膦酰氧基)丁烷-2-基)氨基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-(4-(4-((4-((4-(4-羟基哌啶-1-基)-1-(苯基硫)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-(4-(4-((4-((4-(4-羟基哌啶-1-基)-1-(苯基硫)丁烷-2-基)氨基)-3-(甲基磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-氟-5-(4-(4-((4-((4-(4-羟基哌啶-1-基)-1-(苯基硫)丁烷-2-基)氨基)-3-(甲基磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-(4-(4-((4-((4-(4-羟基哌啶-1-基)-1-(苯基硫)丁烷-2-基)氨基)-3-(硝基苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-氟-5-(4-(4-((4-((4-(4-羟基哌啶-1-基)-1-(苯基硫)丁烷-2-基)氨基)-3-(硝基苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-(4-(4-((4-((4-(4-(羟基甲基)哌啶-1-基)-1-(苯基硫)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-氟-5-(4-(4-((4-((4-(4-羟基甲基)哌啶-1-基)-1-(苯基硫)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-(4-(4-((4-((4-(4-羟基甲基)哌啶-1-基)-1-(苯基硫)丁烷-2-基)氨基)-3-(甲基磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-氟-5-(4-(4-((4-((4-(4-羟基甲基)哌啶-1-基)-1-(苯基硫)丁烷-2-基)氨基)-3-(甲基磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-(4-(4-((4-((4-(4-羟基甲基)哌啶-1-基)-1-(苯基硫)丁烷-2-基)氨基)-3-硝基苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-氟-5-(4-(4-((4-((4-(4-羟基甲基)哌啶-1-基)-1-(苯基硫)丁烷-2-基)氨基)-3-硝基苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-(4-(4-((4-((4-羟基-1-(苯基硫)丁烷-2-基)氨基)-3-(三氟甲基)磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-氟-5-(4-(4-((4-((4-羟基-1-(苯基硫)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-氟-5-(4-(4-((4-((4-羟基-1-(苯基硫)丁烷-2-基)氨基)-3-(甲基磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-(4-(4-((4-((4-羟基-1-(苯基硫)丁烷-2-基)氨基)-3-(硝基苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-氟-5-(4-(4-((4-((4-羟基-1-(苯基硫)丁烷-2-基)氨基)-3-(硝基苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-3-((4-(N-(4-(4-(3-(4-羧基-2-(4-氯苯基)-1-异丙基-5-甲基-1H-吡咯-3-基)-5-氟苯基)哌嗪-1-基)苯基)-氨磺酰基)-2-((三氟甲基)磺酰基)苯基)氨基)-4-(苯基硫)丁基磷酸钠
(R)-5-(4-氯苯基)-4-(3-(4-(4-((4-((4-羟基-1-(苯基硫)丁烷-2-基)氨基)-3-(甲基磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
可以依照此公开作为衰老消解剂或用于治疗衰老相关疾病测试和开发的其它化合物包括表1B中显示的化合物:
表1B
(R)-5-(4-氯苯基)-4-(3-(4-(4-((4-((4-(4-羟基哌啶-1-基)-1-(苯基硫)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1,2-二甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-1-乙基-4-(3-(4-(4-((4-((4-(4-羟基哌啶-1-基)-1-(苯基硫)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-2-甲基-1H-吡咯-3-羧酸
对化合物评估衰老消解和化疗活性
可以在分子水平对此公开中列出这些和其它化合物评估它们以指示它们是供作为活性剂用于制备药物或在人疗法中使用的候选剂的方式运转的能力。
例如,在疗法包括通过Bcl-2,Bcl-xL,Bcl-w,或其它Bcl家族蛋白质触发衰老细胞凋亡的情况下,可以对化合物测试它们抑制一种或多种Bcl蛋白质和它们的各自关联配体之间的结合的能力。实施例1提供用于测定对Bcl同等型的结合的目的的均质测定法(一种不要求分离步骤的测定法)的示例。可以在分子水平对化合物筛选它们与靶同等型相互作用,由此引起衰老消解的能力。实施例2和3提供为了这个目的设计的测定法的示例。
或者或另外,可以对化合物评估特异性杀伤衰老细胞的能力。使培养的细胞与化合物接触,并测定细胞毒性或细胞抑制的程度。可以与化合物对以低密度自由分裂的正常细胞和以高密度处于静止状态的正常细胞的效果比较化合物杀伤或抑制衰老细胞的能力。实施例2和3提供使用人靶组织成纤维细胞IMR90细胞系和HUVEC细胞的衰老细胞杀伤的示例。类似的方案是已知的且可以开发或优化用于测试化合物杀伤或抑制其它衰老细胞和其它细胞类型,诸如癌细胞的能力。
可以在特定疾病的动物模型中进一步筛选在体外有效选择性杀伤衰老细胞的候选Bcl抑制剂。下文实验部分的实施例4,5,6,和7分别提供骨关节炎,眼疾病,肺疾病,和动脉粥样硬化的示例。
或者或另外,可以对化合物评估特异性杀伤癌或肿瘤细胞的能力。使培养的细胞与化合物接触,并测定对细胞的细胞毒性的程度和/或抑制细胞增殖的能力。可以与化合物对培养物中相同起源组织类型的正常细胞的效果比较对癌细胞的效果。还可以在已建立动物模型中对化合物测试它们去除肿瘤,抑制癌细胞生长,和治疗癌症的症状和体征的能力。实施例8提供评估此公开中的化合物作为化疗剂的潜力的体外和体内测定法的示例。
药物的配制
供依照此公开使用的药剂的制备和配制可以并入标准技术,如例如当前版本的Remington:The Science and Practice of Pharmacy中描述的。典型地会为了施用于靶组织(例如通过局部施用)而以增强活性剂进入靶衰老消解细胞及提供最佳效果持续时间,同时最小化副作用或不牵涉所治疗的状况的组织的暴露的方式优化配制剂。
可以通过混合Bcl抑制剂与药学可接受基材或载剂和根据需要的一种或多种药学可接受赋形剂来制备供治疗衰老相关状况和其它疾病中使用的药学制剂。取决于靶组织,配制用于持续或定时释放的药学组合物可能是适宜的。口服定时释放配制剂可包括异构体变体,粘合剂,或包衣的混合物。可注射定时释放配制剂可包括与粘合剂,包囊剂,或微粒组合的活性剂。对于治疗关节疾病,诸如骨关节炎,典型地配制用于关节内施用的药学组合物。对于治疗眼疾病,诸如青光眼,糖尿病性视网膜病或年龄相关黄斑变性(AMD),可以配制用于玻璃体内或前房内施用的组合物。对于治疗肺疾病,可以配制作为气雾剂或用于气管内施用的组合物。
此公开提供商业性产品,其是封装此公开中描述的一种或多种药剂或组合物的单位剂量的试剂盒。此类试剂盒典型地包含一个或多个容器中的药学制剂。可以作为一个或多个单位剂量(或是组合的或是分开的)提供制剂。试剂盒可含有用于在有需要的受试者的靶组织中或周围施用药剂或组合物的装置,诸如注射器。产品还可以含有或伴有描述药物在治疗衰老细胞相关状况中的用途和附带益处的信息性包装插页,和任选地用于治疗性投递组合物的器具或装置。
治疗设计
衰老细胞随年龄而积累,这是由衰老细胞介导的状况在老年人中更加频繁地发生的原因。另外,肺部组织上不同类型的应激可促进衰老细胞的出现和它们表达的表型。细胞应激原包括氧化应激,代谢应激,DNA损伤(例如,作为环境紫外线暴露或遗传病症的结果),癌基因激活,和端粒缩短(源自例如高增殖)。遭受此类应激原的组织可具有更高流行度的衰老细胞,其继而可导致在更早年龄或以更加严重形式呈现某些状况。对某些状况的可遗传易感性提示疾病介导性衰老细胞的积累可能受到遗传成分直接或间接影响,其可导致更早的呈现。
衰老细胞范例的益处之一是成功去除衰老细胞可为受试者提供长期治疗性效果。衰老细胞本质上是非增殖性的,这意味着随后组织中更多衰老细胞的再建群只能通过组织中的非衰老细胞转变成衰老细胞—比简单增殖花费显著更长的过程来发生。作为一般原则,足以自靶组织去除衰老细胞的使用衰老消解剂的疗法的时段(给予单个剂量或多个剂量,例如每天,半周一次,或一周一次,在几天,一周,或数个月的时段上给予)可为受试者提供一段时间的功效(例如两周,一个月,两个月,或更久),期间不施用衰老消解剂,而且受试者经历所治疗的状况的一种或多种不良体征或症状的缓解,减轻,或逆转。
为了用依照此公开的衰老消解剂治疗特定衰老相关状况,治疗方案会取决于衰老细胞的位置和疾病的病理生理学。
适合于治疗的衰老相关状况
此公开的Bcl抑制剂可用于预防或治疗各种衰老相关状况。此类状况会典型地(尽管并非必然地)特征在于与未受影响的组织中此类细胞的频率或此类表达的水平相比,状况的部位中或周围衰老细胞(诸如表达p16和其它衰老标志物的细胞)过多,或p16和其它衰老标志物的表达过多。当前感兴趣的非限制性例子包括治疗骨关节炎,眼疾病,和肺疾病,如下面各节例示的。
骨关节炎的治疗
此公开中列出的任何Bcl抑制剂可开发用于依照此公开治疗骨关节炎。类似地,此公开中列出的Bcl抑制剂可开发用于选择性消除有需要的受试者的关节中或周围的衰老细胞,包括但不限于受到骨关节炎影响的关节。
骨关节炎变性性关节疾病特征在于高机械应力,骨硬化,和滑膜和关节囊的增厚的位点处软骨的原纤维化。原纤维化是局部表面去组织化,牵涉软骨浅表层分裂。早期分裂沿着主要胶原束的轴,与软骨表面相切。软骨内的胶原变成去组织化,而且自软骨表面损失蛋白聚糖。在关节中蛋白聚糖的保护和润滑效果缺失下,胶原纤维变成对降解易感,而且随之发生机械破坏。发生骨关节炎的易感性风险因素包括年龄增长,肥胖,先前的关节损伤,过度使用关节,大腿肌肉弱,和遗传。骨关节炎的症状包括不活动或过度使用后,关节(特别是臀部,膝盖,和下背部)酸痛或僵硬;休息后的僵硬,在运动后消除;和活动后或一天结束时疼痛恶化。
依照此公开的化合物可用于降低或抑制关节中蛋白聚糖层的损失或侵蚀,减轻受影响的关节中的炎症,和促进,刺激,增强,或诱导胶原,例如2型胶原的生成。化合物可引起关节中生成的炎性细胞因子(诸如IL-6)的量或水平降低且炎症减轻。化合物可用于治疗骨关节炎和/或诱导受试者的关节中胶原(例如2型胶原)生成。化合物还可用于降低,抑制,或减少降解关节中的胶原的金属蛋白酶13(MMP-13)的生成,和恢复蛋白聚糖层或抑制蛋白聚糖层的损失和/或降解。使用化合物的治疗由此还可降低侵蚀的可能性,抑制或降低侵蚀,或减缓骨的侵蚀。化合物可以直接施用于骨关节炎关节,例如关节内,表面,透皮,皮内,或皮下。化合物还可恢复关节的强度,改善关节的强度,或抑制关节的强度的下降,和减轻关节疼痛。
眼部状况的治疗
此公开中列出的任何Bcl抑制剂可用于预防或治疗有需要的受试者中的眼部状况,其通过去除受试者的眼中或周围的衰老细胞,由此疾病的至少一种体征或症状的严重程度降低。此类状况包括眼后疾病和眼前疾病二者。类似地,此公开中列出的Bcl抑制剂可开发用于选择性消除有需要的受试者中的眼组织中或周围的衰老细胞。
可依照此公开治疗的眼的疾病包括老视,黄斑变性(包括湿性或干性AMD),糖尿病性视网膜病,和青光眼。
黄斑变性是一种可表征为眼后疾病的神经变性性状况。它引起视网膜中央部分(称作黄斑)中的光受体细胞的损失。黄斑变性可以是干性的或湿性的。干性形式比湿性更加常见,约90%的年龄相关黄斑变性(AMD)患者诊断有干性形式。干性AMD与视网膜色素上皮(RPE)层的萎缩有关,其引起光受体细胞的损失。具有湿性AMD时,新血管可生长在视网膜下方并渗漏血液和流体。异常渗漏的脉络膜新血管形成可引起视网膜细胞死亡,产生中央视力中的盲点。黄斑的Bruch氏膜下面渗出物或“疣”的形成可以是黄斑变性正在出现的身体体征。黄斑变性的症状包括例如感觉到变形和颜色感知变化。
另一种眼后疾病是糖尿病性视网膜病(DR)。依照维基百科,DR的第一阶段是非增殖性的,而且典型地没有实质性症状或体征。NPDR是通过眼底照相术可检测的,其中可以看见微动脉瘤(动脉壁中的微观充血突起)。如果视力有下降的话,可以进行荧光素血管造影术来看眼后。可以清楚地看到视网膜血管变窄或阻断,而且这称作视网膜缺血(缺乏血流)。NPDR的任何阶段可发生黄斑水肿,其中血管将它们的内容物渗漏入黄斑区域。黄斑水肿的症状是两只眼中不同的视力模糊和图像变暗或变形。光学相干断层摄影术能显示黄斑水肿的视网膜变厚(由于流体积累)的区域。在DR的第二个阶段,异常新血管(新血管形成)在眼后形成,作为增殖性糖尿病性视网膜病(PDR)的一部分,其可能破裂和出血(玻璃体出血)和使视力模糊。在眼底镜检查时,临床医师会看到棉线斑点,火焰出血(诺维梭菌(Clostridium novyi)的α-毒素也引起类似损害),和点印迹出血。
用此公开的衰老消解剂治疗眼后疾病的益处可包括抑制或延迟状况的不良特征,诸如异常新血管形成,病原性血管发生,血管闭塞,眼内出血,视网膜损伤,和视力丧失。可以在眼中或周围施用衰老消解剂,例如通过眼内,玻璃体内,或球后注射。最佳地,一些病理生理学会有逆转,诸如恢复功能性血管系统,功能血管发生,视网膜再生长或恢复,及部分程度的视力改善。
老视是一种年龄相关状况,其中因为正常眼的调节速度和幅度随年龄增长而降低,眼展现在近物上聚焦的能力逐渐减弱。晶状体的弹性丧失和睫状肌的收缩性丧失可引起老视。晶状体前囊和晶状体后囊的机械特性的年龄相关变化提示晶状体后囊的机械强度随年龄而显著降低,这是组织的构成的变化的后果。晶状体囊的主要结构成分是组织成三维分子网络的基底膜IV型胶原。胶原IV,纤连蛋白,和层板(lamina)对眼内晶状体的粘附能抑制细胞迁移且能降低PCO的风险。
此公开提供的衰老消解剂可减缓IV型胶原网络的去组织化,降低或抑制上皮细胞迁移且还能延迟老视的发作或降低或减缓状况的进行性严重程度。它们对于白内障后手术也可能是有用的,用于降低PCO发生的可能性。
青光眼和其它眼前疾病也可能适合于用此公开提供的衰老消解剂治疗。在正常情况下,清澈的流体流入和流出眼的前部,称作前房。在具有开角型/广角型青光眼的个体中,清澈的流体排出太慢,导致眼内的压力升高。如果留着不治疗的话,眼中的高压能随后损害视神经且能导致完全失明。周围视力的丧失是由视网膜中的神经节细胞死亡引起的。
疗法可能的益处包括眼内压降低,眼液经由小梁网络排出改善,和抑制或延迟所致视力丧失。可以在眼中或周围施用衰老消解剂,例如通过眼内或前房内注射或在表面配制剂中。可以通过自动化视野检查,前房角镜检查,成像技术,扫描激光断层摄影术,HRT3,激光旋光法,GDX,眼相干断层照相,检眼镜检查,和测定中央角膜厚度的厚度计测量来监测疗法的效果。
肺部状况的治疗
此公开中列出的任何Bcl抑制剂可开发用于依照此公开治疗肺部疾病。类似地,此公开中列出的Bcl抑制剂可开发用于选择性消除有需要的受试者的肺中或周围的衰老细胞。可治疗的肺部状况包括特发性肺纤维化(IPF),慢性阻塞性肺病(COPD),哮喘,囊性纤维化,支气管扩张,和肺气肿。
COPD是一种通过肺组织破坏,肺气肿,和小气道功能障碍,阻塞性细支气管炎所致持续差气流来定义的肺病。COPD的主要症状包括呼吸急促,喘鸣,胸闷,长期咳嗽,和过量痰生成。来自香烟烟雾激活的嗜中性细胞和巨噬细胞的弹性蛋白酶能分解肺泡结构的细胞外基质,导致气隙变大和呼吸能力损失。COPD可以是由例如烟草烟雾,香烟烟雾,雪茄烟雾,二手烟雾,烟斗烟雾,职业暴露,暴露于灰尘,烟雾,烟尘,和污染引起的,发生数十年,由此牵涉老化作为发生COPD的风险因子。
引起肺损伤的过程包括例如由烟草烟雾中的高浓度自由基生成的氧化应激,对气道中的刺激物的炎症反应所致的细胞因子释放,和烟草烟雾和自由基对抗蛋白酶酶类的损害,容许蛋白酶损害肺。遗传易感性也可能促成疾病。在约1%的具有COPD的人中,疾病源自引起在肝中低水平生成α-1-抗胰蛋白酶的遗传病症。α-1-抗胰蛋白酶在正常情况下分泌入血流以帮助保护肺。
肺纤维化是一种慢性和进行性肺病,特征在于肺变硬和结疤,其可导致呼吸衰竭,肺癌,和心力衰竭。纤维化与上皮修复有关。成纤维细胞受到激活,细胞外基质蛋白质的生成升高,而且变成收缩性成肌纤维细胞的转分化促进伤口收缩。临时基质阻塞受损上皮并为上皮细胞迁移提供支架,牵涉上皮-间充质转化(EMT)。与上皮损伤有关的血液损失诱导血小板激活,生长因子生成,和急性炎症反应。正常情况下,上皮屏障愈合且炎症反应消退。然而,在纤维化疾病中,成纤维细胞反应持续,导致未消退的伤口愈合。形成成纤维细胞灶是疾病的一个特征,反映正在发生的纤维发生的位置。
有风险发生肺纤维化的受试者包括例如暴露于环境或职业污染物的受试者,诸如石棉沉着病和硅沉着病;那些吸烟的;那些具有结缔组织疾病的,诸如RA,SLE,硬皮病,结节病,或韦格纳氏肉芽肿病;那些具有感染的;那些服用某些药疗的,包括例如胺碘酮,博来霉素,白消安,甲氨蝶呤,和硝基呋喃妥因;那些遭受胸部放射疗法的;和那些家族成员具有肺纤维化的。
可通过使用依照此公开的化合物来治疗的其它肺部状况包括肺气肿,哮喘,支气管扩张,和囊性纤维化。肺部疾病也可以因烟草烟雾,职业暴露于灰尘,烟雾,或烟尘,感染,或促成炎症的污染物而加剧。
肺疾病的症状可包括呼吸短促,喘鸣,胸闷,因肺中粘液过多不得不早上首先清理嗓子,一种慢性咳嗽,产生痰,可以是透明,白色,黄色或浅绿色的,发绀,频繁的呼吸道感染,精力不足,和意外体重减轻。肺纤维化的症状可包括呼吸急促,特别是在运动期间;干,频咳;快,浅呼吸;逐渐,意外体重减轻;疲劳;关节和肌肉疼痛;和手指或脚趾杵状变。
可以测定治疗之前,期间,和之后的肺功能,例如通过测量呼气储备容量(ERV),用力肺活量(FVC),用力呼气量(FEV),总肺活量(TLC),肺活量(VC),残气量(RV),和功能残气量(FRC)。可以使用一氧化碳扩散量(DLCO)来测量跨越肺泡毛细血管膜的气体交换。可以测量运动能力作为替代指标。还可以测量外周毛细血管氧饱和度(SpO2):正常氧水平典型地在95%和100%之间。90%以下的SpO2水平提示受试者具有低氧血症。80%以下的值认为是紧要的且要求干预以维持脑和心功能及避免心脏或呼吸停止。
治疗的益处可包括抑制任何这些效应进展或逆转任何这些效应。施用衰老消解剂可以是系统性的,或在肺中或周围的部位处局部的:例如,通过作为气雾剂或粉剂吸入,或通过插管。最佳地,药剂会改善SpO2水平和运动能力。
动脉粥样硬化的治疗
衰老消解化合物可用于治疗动脉粥样硬化:例如通过抑制受试者中动脉粥样硬化斑块的形成,扩大,或进展。衰老消解化合物还可用于增强受试者的一根或多根血管中存在的动脉粥样硬化斑块的稳定性,由此抑制它们破裂和阻塞血管。
动脉粥样硬化特征在于在中等尺寸和大动脉的内腔上侵入的斑块状内膜斑块,粥样斑;斑块含有脂质,炎症细胞,平滑肌细胞,和结缔组织。动脉粥样硬化可影响大和中等尺寸动脉,包括冠状动脉,颈动脉,和脑动脉,主动脉及其分支,和四肢的主要动脉。
动脉粥样硬化可导致动脉壁厚度增加。当斑块的生长或破裂减少或阻塞血流时发生症状;而且症状可以随受影响的动脉而变化。动脉粥样硬化斑块可以是稳定的或不稳定的。稳定的斑块消退,保持静止,或缓慢生长,有时持续数十年,直至它们能引起狭窄或阻塞。不稳定的斑块容易遭受自发的侵蚀,裂缝,或破裂,引起急性血栓形成,阻塞,和梗塞,很久之后它们引起血液动力学显著狭窄。临床事件可源自不稳定的斑块,它们在血管造影上并不表现严重;因而,斑块稳定化可能是降低发病率和死亡率的一种方式。斑块破裂或侵蚀可导致重大心血管事件,诸如急性冠状动脉综合征和中风。破裂的斑块可具有更多含量的脂质,巨噬细胞,且具有比完整斑块要薄的纤维帽。
动脉粥样硬化和其它心血管疾病的诊断可以基于症状,例如心绞痛,胸部压力,臂或腿麻木或无力,说话困难或口齿不清,面部肌肉下垂,腿疼,高血压,肾衰竭和/或勃起功能障碍,医学史,和/或患者的体检。诊断可以通过血管造影,超声检查,或其它成像检查来确认。有风险发生心血管疾病的受试者包括那些具有任何一种或多种易感性因素(诸如心血管疾病的家族史)的,和那些具有其它风险因素的,例如包括高血压,血脂异常,高胆固醇,糖尿病,肥胖和吸烟,久坐的生活方式,和过度紧张的易感性因素。可以例如通过血管造影,心电图,或应激测试来评估状况。
用衰老消解剂治疗的潜在益处包括缓解或停止状况的一种或多种体征或症状的进展,诸如斑块的频率,斑块覆盖的血管的表面积,心绞痛,和运动耐力降低。
定义
“衰老细胞”一般认为衍生自典型地复制的细胞类型,但是因老化或引起细胞状态变化的其它事件而不再能复制。取决于语境,衰老细胞可以以表达p16,或至少一种选自p16,衰老相关β-半乳糖苷酶,和脂褐素的标志物;有时两种或更多种这些标志物,和衰老相关分泌谱(SASP)的其它标志物,诸如但不限于白介素-6,和炎性,血管发生性和细胞外基质修饰蛋白来鉴定。除非另有明确说明,权利要求中提到的衰老细胞不包括癌细胞。
“衰老有关”,“衰老相关”或“年龄相关”疾病,病症,或状况是呈现对受试者不利的一种或多种症状或体征的生理状况。如果状况是“至少部分由衰老细胞引起或介导”的话,它是“衰老相关”的。这意味着受影响组织中或周围SASP的至少一种成分在状况的病理生理学中发挥作用,使得消除受影响组织中的至少一些衰老细胞导致不良症状或体征的实质性缓解或减轻,对患者有益。能使用依照此公开的方法和产品潜在治疗或管理的衰老相关病症包括此公开中和讨论中提到的在先公开中提到的病症。除非另有明确说明,该术语不包括癌症。
蛋白质功能或Bcl功能的抑制剂是以实质性程度阻止靶细胞中早就表达的靶蛋白质发挥该蛋白质或Bcl家族成员在正常情况下在靶细胞中所发挥的酶,结合,或调节功能的化合物。这导致消除靶细胞或使得细胞对另一化合物或事件的毒性更加易感。如果当在依照下文实施例1的测定法中测试时化合物具有小于1,000nM(1.0μM)的IC50的话,它符合此公开中的“Bcl抑制剂”或“抑制Bcl活性”的化合物。小于100nM或10nM,或100nM和1nM之间的活性常常是优选的,取决于语境。
术语“Bcl”或“Bcl蛋白质”指Bcl蛋白质的家族,以Bcl-2,Bcl-xL,和Bcl-w例示。此公开的Bcl抑制剂会能够抑制Bcl-2,Bcl-xL,和Bcl-w至少之一。典型地但非必须地,这些Bcl蛋白质之一的抑制剂会以一些程度抑制其它两种。可以对此公开中提供的化合物测试任何Bcl家族成员的活性,以鉴定对Bcl-2,Bcl-xL,或Bcl-w潜在特异性且具有抑制性活性的化合物。此类抑制剂会具有比它对表中的其它两种Bcl家族成员的IC50好至少10倍的对来自此表的靶Bcl的IC50。
如果化合物,组合物或药剂消除衰老细胞,优先于相同组织类型的复制性细胞,或缺乏SASP标志物的静止细胞的话,它典型地称作“衰老消解”的。或者或另外,如果化合物或组合降低在状况的初始呈现或行进病理中发挥作用,或抑制它的解决的作为衰老相关分泌表型的一部分的病理性可溶性因子或介导物的释放的话,可有效使用它。在这个方面,术语“衰老消解”指功能抑制,使得可以以相似方式使用主要通过抑制而非消除衰老细胞而起作用的化合物(衰老细胞抑制剂)从而带来益处。此公开中的模式衰老消解组合物和药剂当在依照下文实施例2的测定法中测试时具有小于1μM的EC50。小于0.1μM,或1μM和0.1μM之间的活性可能是优选的。选择性指数(SI)(衰老细胞与相同组织类型的非衰老细胞相比的EC50)可以是好于1,2,5,或10,取决于语境。
自混合细胞群体或组织选择性去除或“消除”衰老细胞并不要求去除所有携带衰老表型的细胞:只是治疗后保留的组织中初始的衰老细胞的比例实质性高于治疗后保留的组织中初始的非衰老细胞的比例。
依照此公开的状况的成功“治疗”可以具有对所治疗的受试者有益的任何效果。这包括降低状况或其所致任何不良体征或症状的严重程度,持续时间,或进展。治疗也可能是不成功的,导致状况的典型体征和症状没有改善。疗法的一项并行目标是最小化对靶组织或所治疗受试者中的其它部位的不良作用。在一些情况中,也可以使用衰老消解剂来阻止或抑制受试者因例如遗传易感性或医学史而对其易感的状况的呈现。
“治疗有效量”是本公开的化合物的量,其(i)治疗特定疾病,状况,或病症,(ii)削弱,改善,或消除特定疾病,状况,或病症的一种或多种症状,(iii)阻止或延迟本文中描述的特定疾病,状况,或病症的一种或多种症状发作,(iv)阻止或延迟特定疾病,状况或病症进展,或(v)至少部分逆转在治疗前由状况引起的损害。
“磷酸化”形式的化合物是携带一个或多个经由氧原子(典型地但非必须地,其在磷酸化前存在于分子上)共价结合至核心结构的磷酸根基团的化合物。例如,一个或多个-OH或-COOH基团可以是取代的,氢被磷酸根基团代替,或是-OPO3H2或是-CnPO3H2(其中n是1至4)。在一些磷酸化形式中,可以在体外去除磷酸根基团(例如通过酶解),在该情况中磷酸化形式可以是非磷酸化形式的前药。非磷酸化形式没有此类磷酸根基团。去磷酸化形式是磷酸化分子在去除至少一个磷酸根基团后的衍生物。
依照此公开的“小分子”Bcl抑制剂具有小于20,000道尔顿,而且常常小于10,000,5,000,或2,000道尔顿的分子量。小分子抑制剂不是抗体分子或寡核苷酸,而且典型地具有不多于5个氢键供体(氮-氢和氧-氢键的总数),和不多于10个氢键受体(所有氮或氧原子)。
“前药”指活性剂的衍生物,其在身体内要求转化以释放活性剂。转化可以是酶促转化。有时,转化是环化转化,或酶促转化和环化转化的组合。前药通常但非必须是无药学活性的,直至转变成活性剂。
除非另有说明或要求,本公开中提到的每种化合物结构包括具有相同结构的共轭酸和碱,那些化合物的结晶和无定形形式,药学可接受盐,和前药。这包括例如化合物的多晶型物,溶剂合物,水合物,未溶解的多晶型物(包括无水物),和磷酸化和未磷酸化形式。
援引加入
出于其中有效的美国和其它地区的所有目的,据此通过援引将此公开中引用的每份和每一份出版物和专利文件完整收入本文用于所有目的,程度与就像具体和个别指出通过援引将每份出版物或文件收入本文相同。
据此将美国专利10,130,628(Laberge等人)和US 20170266211 A1(David等人)收入本文用于所有目的,包括但不限于衰老消解剂的鉴定和配制,和它们用于治疗认为至少部分由衰老细胞介导的各种状况的用途。据此通过援引将美国专利8,691,184,9,096,625,和9,403,856(Wang等人)完整收入本文用于所有目的,包括Bcl文库中的化合物的特征,它们的制备和用途。据此将美国专利申请15/675,171(2017年8月11日提交)和62/579,793(2017年10月31日提交)收入本文用于所有目的,包括但不限于能够消除或降低衰老细胞的活性和治疗各种眼部状况的化合物的鉴定,配制,和使用。
实施例
实施例1:测量Bcl抑制
可以通过直接结合在分子水平测量候选化合物抑制Bcl-2和Bcl-xL活性的能力。这种测定法使用一种由PerkinElmer Inc.(Waltham,Massachusetts)销售的基于氧通道的均质测定法技术:见Eglin et al.,Current Chemical Genomics,2008,1,2-10。将测试化合物与靶Bcl蛋白质和用生物素标记的呈递相应关联配体的肽组合。然后将混合物与携带链霉亲合素的发光供体珠和发光受体珠组合,如果化合物抑制肽结合Bcl蛋白质的话,其成比例降低发光。Bcl-2,Bcl-xL和Bcl-w自Sigma-Aldrich Co.(St.Louis,Missouri)可得。生物素化BIM肽(Bcl-2的配体)和BAD肽(Bcl-xL的配体)记载于US 2016/0038503 A1。链霉亲合素供体珠和抗6XHis受体珠自PerkinElmer可得。
为了进行测定法,在DMSO中制备化合物的1:4稀释系列,然后在测定缓冲液中1:100稀释。在96孔PCR板中,依次组合下面各项:10μL肽(120nM BIM或60nM BIM),10μL测试化合物,和10μL Bcl蛋白质(0.8nM Bcl-2/W或0.4nM Bcl-XL)。将测定板在黑暗中于室温温育24小时。次日,组合供体珠和受体珠,并添加5μL至每个孔。在黑暗中温育30分钟后,使用读板仪测量发光,并测定每种测试化合物的亲和力或抑制程度。
实施例2:在成纤维细胞中测量衰老消解活性
人成纤维细胞IMR90细胞可以以名称CCL-186自美国典型培养物保藏中心获得。在3%O2,10%CO2,和~95%湿度的气氛中在含有FBS和青霉素/链霉素的DMEM中以<75%汇合度维持细胞。将细胞分组:经照射细胞(在照射后在使用前培养14天)和静止细胞(在使用前以高密度培养4天)。
在第0天,如下制备经照射细胞。清洗IMR90细胞,以50,000个细胞/mL的密度放置在T175烧瓶中,并以10-15Gy照射。照射后,在96孔板中以100μL分配细胞。在第1,3,6,10,和13天,抽吸每个孔中培养基并用新鲜培养基替换。
在第10天,如下制备静止健康细胞。清洗IMR90细胞,与3mL TrypLE含有胰蛋白酶的试剂(Thermofisher Scientific,Waltham,Massachusetts)组合并培养5分钟直至细胞变圆并开始自板脱离。分散细胞,计数,并以50,000个细胞/mL的浓度在培养基中制备。在96孔板的每个孔中分配100μL细胞。在第13天更换培养基。在第14天,如下组合测试抑制剂化合物与细胞。在96孔PCR板中以最终期望浓度的200倍制备每种测试化合物的DMSO稀释系列。临使用前,将DMSO储液1:200稀释入预温热的完全培养基。自每个孔中的细胞抽吸培养基,并添加100μL/孔含有化合物的培养基。
将用于测试的候选衰老消解剂与细胞一起培养6天,在第17天用新鲜培养基和相同化合物浓度替换培养培养基。将Bcl-2抑制剂与细胞一起培养3天。测定系统利用热稳定萤光素酶的特性来实现生成稳定发光信号而同时抑制细胞裂解期间释放的内源ATP酶的反应条件。在培养时段结束时,添加100μL试剂(Promega Corp.,Madison,Wisconsin)至每个孔。将细胞板在定轨摇床上放置30秒,并测量发光。
实施例3:在HUVEC细胞和其它衰老细胞中测量衰老消解活性
将来自单批的人脐带静脉(HUVEC)细胞在补充有来自ATCC的内皮细胞生长试剂盒TM-VEGF的血管细胞基础培养基中扩充至大约八倍群体倍增,然后冻存。在测定法开始前9天,融化用于衰老群体的细胞并以大约27,000/cm2接种。在具有5%CO2和3%O2的增湿温箱中培养所有细胞并每48小时更换培养基。接种后2天,照射细胞,递送来自X射线源的12Gy放射。测定法开始前3天,融化用于非衰老群体的细胞并像衰老群体那样接种。测定法前1天,用胰蛋白酶处理所有细胞并接种入384孔板,以55μL/孔的终体积在分开的板中5,000/孔衰老细胞和10,000/孔非衰老。在每块板中,中央的308个孔含有细胞而外周的孔装有70μL/孔去离子水。
在测定法那天,将化合物自10mM储液稀释入培养基以提供最高浓度工作储液,然后在培养基中进一步稀释其等分试样以提供剩余两种工作储液。为了启动测定法,添加5μL工作储液至细胞板。最终测试浓度为20,2,和0.2μM。在每块板中,以单一浓度一式三份测定100种测试化合物连同阳性对照的3个孔和无处理(DMSO)对照的5个孔。添加化合物后,将板放回温箱达3天。
通过使用CellTiter-GloTM试剂(Promega)测量总ATP浓度来间接评估细胞存活。用EnSpireTM读板仪(Perkin Elmer)量化所得发光。作为相对于相同板的无处理对照的百分比计算每种浓度的化合物的相对细胞存活力。
对于潜在先导化合物的跟踪剂量响应,如上文所述制备衰老和非衰老细胞的384孔板。作为DMSO中的10点1:3稀释系列制备化合物,然后在培养基中稀释至12倍。然后添加5μL这种工作储液至细胞板。温育3天后,如上所述计算相对于DMSO对照的细胞存活。一式四份实施所有测量。
可以使用其它细胞系和原代细胞培养物作为IMR90成纤维细胞或HUVEC细胞的备选,对准体内预期靶组织。一个例子是使用培养的人视网膜微血管内皮细胞(HRMEC)来筛选旨在用于治疗眼疾病的化合物。依照用于选定细胞系的已知方案培养细胞,并以相似方式照射以使得它们衰老。
实施例4:骨关节炎模型中衰老消解剂的功效
这个实施例例示在骨关节炎的治疗的小鼠模型中测试MDM2抑制剂。经适当修改后它可以适应测试和开发供临床疗法中使用的Bcl抑制剂。
如下实行该模型。C57BL/6J小鼠经历手术以切割一个后肢的前十字韧带以诱导该肢的关节中的骨关节炎。在手术后第3周和第4周期间,通过关节内注射用5.8μg Nutlin-3A(n=7)每个操作的膝处理小鼠,q.o.d.,达2周。在手术后4周结束时,对小鼠的关节监测衰老细胞的存在,评估功能,监测炎症标志物,和经历组织学评估。
所实施的研究中包括2个对照组的小鼠:一个组包含经历假手术(即,除了切割ACL以外遵循手术规程)且与GCV(更昔洛韦)处理组平行关节内注射媒介的C57BL/6J或3MR小鼠(n=3);而一个组包含经历ACL手术且与GCV处理组平行接受关节内注射媒介的C57BL/6J或3MR小鼠(n=5)。对来自Nutlin-3A处理小鼠的小鼠来自操作关节的RNA分析SASP因子(mmp3,IL-6)和衰老标志物(p16)的表达。实施qRT-PCR以检测mRNA水平。
图2A,2B,和2C分别显示组织中p16,IL-6,和MMP13的表达。OA诱导手术与这些标志物升高的表达相关。用Nutlin-3A处理降低表达回到对照的水平以下。用Nutlin-3A处理自关节清理衰老细胞。
手术后4周通过负重测试评估肢的功能以确定小鼠偏爱哪条腿。在进行测量前容许小鼠适应腔室至少三次。在腔室内部操纵小鼠,在每个秤(scale)上以一只后爪站立。在3秒时段上测量放置在每条后肢上的重量。在每个时间点对每只动物进行至少三次分开的测量。作为放置在操作肢对对侧未操作肢上的重量的百分比表述结果。
图3A显示功能研究的结果。经历骨关节炎诱导手术的未处理小鼠偏爱未操作后肢胜过操作后肢(Δ)。然而,在经历手术的小鼠中用Nutlin-3A清理衰老细胞消除这种效应(▽)。
图3B,3C,和3D显示来自这些实验的关节组织的组织病理学。通过ACL手术诱导的骨关节炎引起蛋白聚糖层遭到破坏。使用Nutlin-3A清理衰老细胞完全消除这种效应。
实施例5:糖尿病性视网膜病的模型中衰老消解剂的功效
这个实施例例示在眼后疾病,具体是糖尿病性视网膜病的治疗的小鼠模型中测试Bcl抑制剂。经适当修改后它可以适应测试供临床疗法中使用的衰老消解剂。
在小鼠氧诱导的视网膜病(OIR)模型(Scott and Fruttiger,Eye(2010)24,416-421,Oubaha et al,2016)中研究模型化合物UBX1967(一种Bcl-xL抑制剂)的功效。自出生后第7天(P7)至P12使C57Bl/6小鼠幼仔和它们的CD1养母暴露于高氧环境(75%O2)。在P12,对动物玻璃体内注射1μl在1%DMSO,10%Tween-80,20%PEG-400中配制的测试化合物(200,20,或2uM),并返回室内空气直至P17。在P17摘除眼并解剖视网膜用于血管染色或qRT-PCR。为了测定血管或新血管面积,将视网膜平放,并用在1mM CaCl2中1:100稀释的异凝集素B4(IB4)染色。为了定量测量衰老标志物(例如Cdkn2a,Cdkn1a,Il6,Vegfa),实施qPCR。分离RNA并通过逆转录生成cDNA,其用于选定转录物的qRT-PCR。
图4A和4B显示在所有剂量水平玻璃体内(ITT)施用UBX1967导致新血管形成和血管闭塞的程度的统计学显著改善。
还在链唑霉素(STZ)模型中研究UBX1967的功效。对6至7周的C57BL/6J小鼠称重并测量它们的基线血糖(Accu-ChekTM,Roche)。以55mg/kg连续5天对小鼠腹膜内注射STZ(Sigma-Alderich,St.Louis,MO)。对年龄匹配对照注射仅缓冲液。最后一次STZ注射后1周再次测量血糖,而且,如果它们的非空腹血糖比17mM(300mg/L)要高的话,认为小鼠是糖尿病性的。在STZ施用后8和9周对STZ处理糖尿病性C57BL/6J小鼠玻璃体内注射1μl UBX1967(2μM或20μM,在0.015%聚山梨酯-80,0.2%磷酸钠,0.75%氯化钠,pH 7.2中作为悬浮液配制)。在STZ处理后10周实施视网膜Evans蓝渗透测定法。
图4C和4D显示这种方案的结果。玻璃体内(IVT)施用UBX1967后视网膜和脉络膜血管渗漏在两个剂量水平均改善血管通透性。
在与青光眼有关的测试中可以使用视网膜神经节细胞损伤的其它模型,其中认为升高的眼内压(IOP)引起视网膜神经节细胞损失和视神经损伤。在临床前种类中,升高的前房压可导致视网膜神经元损失,如数种已建立模型中报告的,包括磁性微珠阻塞(Ito etal.,Vis Exp.2016(109):53731)和其它青光眼模型(Almasieh and Levin,Annu Rev VisSci.2017)。另外,已经证明缺血-再灌注引起可导致细胞衰老的视网膜损伤。可使用此类模型中视网膜衰老的存在来监测玻璃体内注射测试化合物后衰老消解的效果。
实施例6:肺部疾病模型中衰老消解剂的功效
这个实施例例示在肺疾病的治疗的小鼠模型中测试抑制剂:具体而言,一种用于特发性肺纤维化(IPF)的模型。经适当修改后它可以适应测试和开发供临床疗法中使用的Bcl抑制剂。作为针对慢性阻塞性肺病(COPD)的模型,使小鼠暴露于香烟烟雾。
通过衰老细胞清理,肺功能,和组织病理学来评估衰老消解剂对暴露于烟雾的小鼠的作用。
这项研究中使用的小鼠包括3MR株系,记载于US 2017/0027139 A1和Demaria etal.,Dev Cell.2014December 22;31(6):722-733。3MR小鼠具有编码将前药更昔洛韦(GCV)转变成对细胞致命的化合物的胸苷激酶的转基因。转基因中的酶置于p16启动子控制下,其引起它在衰老细胞中特异性表达。用GCV处理小鼠消除衰老细胞。
这项研究中使用的其它小鼠包括INK-ATTAC株系,记载于US 2015/0296755 A1和Baker et al.,Nature 2011Nov 2;479(7372):232-236。INK-ATTAC小鼠具有编码在p16启动子控制下的可开关胱天蛋白酶8的转基因。胱天蛋白酶8可以通过用开关化合物AP20187处理小鼠来激活,其后胱天蛋白酶8直接在衰老细胞中诱导凋亡,自小鼠消除它们。
为了进行实验,将6周龄3MR(n=35)或INK-ATTAC(n=35)小鼠长期暴露于自Teague TE-10系统生成的香烟烟雾,该系统是一种自动控制香烟吸烟机器,在腔室中产生侧流和主流香烟烟雾的组合,输送至收集和混合腔室,其中混合不同量的空气与烟雾混合物。COPD方案改编自约翰·霍普金斯大学的COPD核心设施(Rangasamy et al.,2004,J.Clin.Invest.114:1248-1259;Yao et al.,2012,J.Clin.Invest.122:2032-2045)。
小鼠接受总共每天6小时的香烟烟雾暴露,一周5天,达6个月。每支点燃的香烟(3R4F研究香烟每支香烟含有10.9mg总颗粒物(TPM),9.4mg焦油,和0.726mg尼古丁,和11.9mg一氧化碳[University of Kentucky,Lexington,KY])抽吸2秒,每分钟一次,总共8次抽吸,流速1.05L/min,用于提供35cm3的标准抽吸。调节烟雾机器,通过一次闷烧2支香烟以产生侧流烟雾(89%)和主流烟雾(11%)的混合物。对烟雾腔室气氛监测总悬浮颗粒(80-120mg/m3)和一氧化碳(350ppm)。
在第7天开始,分别用AP20187(每周3次)或更昔洛韦(连续5天处理,继以16天停药,重复直至实验结束)处理(10只)INK-ATTAC和(10只)3MR小鼠。相等数目的小鼠接受相应的媒介。均匀分拆剩余30只小鼠(15只INK-ATTAC和15只3MR),每种遗传修饰株系5只置于三个不同处理组。一组(n=10)接受Nutlin-3A(25mg/kg,溶解在PBS中的10%DMSO/3%Tween-20TM中,处理连续14天,继以停药14天,重复直至实验结束)。一组(n=10)接受ABT-263(Navitoclax)(100mg/kg,溶解在15%DMSO/5%Tween-20中,处理连续7天,继以停药14天,重复直至实验结束),而最后一组(n=10)仅接受用于ABT-263的媒介(15%DMSO/5%Tween-20),继以与ABT-263相同的处理方案。使用另外70只不接受暴露于香烟烟雾的动物作为实验的对照。
2个月的香烟烟雾(CS)暴露后,通过使用MouseSTAT PhysioSuiteTM脉冲血氧仪(Kent Scientific)监测氧饱和度来评估肺功能。用异氟烷(1.5%)麻醉动物并应用脚趾夹。对小鼠监测30秒并计算这个持续时间上的平均外周毛细血管氧饱和度(SpO2)测量值。
图5显示结果。2个月的香烟烟雾暴露后,经由AP2018,更昔洛韦,ABT-263(Navitoclax),或Nutlin-3A清理衰老细胞导致与未处理对照相比小鼠中的SpO2水平的统计学显著升高。
实施例7:当系统施用时动脉粥样硬化中衰老消解剂的功效
这个实施例例示在动脉粥样硬化的治疗的小鼠模型中测试MDM2抑制剂。系统而非局部施用测试化合物。模型是在LDLR-/-株系的小鼠中进行的,其是低密度脂蛋白受体缺陷的。经适当修改后这里描述的实验可以适应测试和开发供临床疗法中使用的其它类型的抑制剂。
在第0周开始并贯穿研究,对2个组的LDLR-/-小鼠(10周)喂食42%卡路里来自脂肪的高脂肪饮食(HFD)(Harlan Teklad TD.88137)。对2个组的LDLR-/-小鼠(10周)喂食正常食物(-HFD)。第0-2周,用Nutlin-3A(25mg/kg,腹膜内)处理一组HFD小鼠和-HFD小鼠。一个处理周期是处理14天,休息14天。对一组HFD小鼠和一组-HFD小鼠施用媒介。在第4周(时间点1),处死一组小鼠并评估斑块中衰老细胞的存在。对于一些剩余小鼠,第4-6周重复Nutlin-3A和媒介施用。在第8周(时间点2),处死小鼠并评估斑块中衰老细胞的存在。第8-10周用Nutlin-3A或媒介处理剩余小鼠。在第12周(时间点3),处死小鼠并评估斑块的水平和斑块中衰老细胞的数目。
在喂食HFD且在时间点1用Nutlin-3A或媒介处理的LDLR-/-小鼠中测量血浆脂质水平,与喂食-HFD的小鼠比较(n=3每组)。午后收集血浆并分析循环脂质和脂蛋白。
在时间点1结束时,处死喂食HFD并用Nutlin-3A或媒介处理的LDLR-/-小鼠(n=3,所有组),并解剖主动脉弓用于RT-PCR分析SASP因子和衰老细胞标志物。将值针对GAPDH标准化并表述为对正常饮食的年龄匹配,媒介处理LDLR-/-小鼠的倍数变化。数据显示一个处理周期后在喂食HFD的LDLR-/-小鼠中用Nutlin-3A清理衰老细胞降低数种SASP因子和衰老细胞标志物,MMP3,MMP13,PAI1,p21,IGFBP2,IL-1A,和IL-1B的表达。
在时间点2结束时,处死喂食HFD并用Nutlin-3A或媒介处理的LDLR-/-小鼠(n=3,所有组),并解剖主动脉弓用于RT-PCR分析SASP因子和衰老细胞标志物。将值针对GAPDH标准化并表述为对正常饮食的年龄匹配,媒介处理LDLR-/-小鼠的倍数变化。数据显示HFD小鼠内的主动脉弓中一些SASP因子和衰老细胞标志物的表达。在喂食HFD的LDLR-/-小鼠中用多个处理周期的Nutlin-3A清理衰老细胞降低大多数标志物的表达。
在时间点3结束时,处死喂食HFD并用Nutlin-3A或媒介处理的LDLR-/-小鼠(n=3,所有组),并解剖主动脉并用Sudan IV染色以检测脂质的存在。通过MRI分析小鼠的身体构成,并通过HemavetTM对循环血细胞计数。
图6显示结果。用Nutlin-3A处理将降主动脉中斑块覆盖的表面积降低约45%。血小板和淋巴细胞计数在Nutlin-3A和媒介处理的小鼠之间是相等的。用Nutlin-3A处理还降低喂食高脂肪饮食的小鼠中的质量和身体脂肪构成。
实施例8:在体外和在体内测量对癌细胞的细胞毒性
可以在白介素-3(IL-3)依赖性前淋巴细胞FL5.12鼠细胞系中评估化合物的细胞活性。通过上调促凋亡因子Bim和Puma,IL-3的撤除诱导FL5.12凋亡。通过隔绝Bim和Puma,Bcl-2(FL5.12-Bcl-2)或Bcl-xL(FL5.12-Bcl-xL)的过表达针对IL-3撤除的效果提供保护。化合物逆转由Bcl-2或Bcl-xL的过表达提供的保护。化合物在IL-3的存在下在引发细胞死亡中无效,其中FL5.12细胞没有遭受促凋亡刺激。在胱天蛋白酶抑制剂ZVAD存在下可以削弱在IL-3撤除下化合物杀伤FL5.12-Bcl-2或FL5.12-Bcl-xL细胞的能力,指示细胞杀伤是胱天蛋白酶依赖性的。
可以进行免疫共沉淀研究以确定BH3模拟物诱导的细胞毒性是否可归于细胞内Bcl-2家族蛋白质-蛋白质相互作用的破坏。化合物诱导FL5.12-Bcl-xL细胞中Bim:Bcl-xL相互作用的剂量依赖性降低。对FL5.12-Bcl-2细胞中Bim:Bcl-2复合物的破坏也观察到相似的结果,指示化合物通过削弱Bcl-xL和Bcl-2隔绝促凋亡因子(诸如Bim)的能力来恢复IL-3依赖性细胞死亡。
可以使用其它已建立细胞系在类似测定法中测试此公开中列出的化合物特异性杀伤癌细胞的能力。这些包括HeLa细胞,OVCAR-3,LNCaP,和自Millipore Sigma(Burlington MA,U.S.A.)可得的任何已认证癌细胞系。如果化合物在比相同组织类型的非癌性细胞低至少5倍,优选25或100倍的浓度对癌细胞致死的话,它们特异性杀伤癌细胞。对照细胞具有与所测试的癌细胞系相似的形态特征和细胞表面标志物,但是没有癌症的迹象。
在体内,依照使用者特别感兴趣的癌症类型,在自敏感SCLC(H889)和血液学(RS4;11)细胞系或使用其它肿瘤形成性癌细胞系建立的体侧异种移植物模型中评估化合物。当口服或静脉内给药时,化合物诱导迅速且完全的肿瘤响应(CR),其在所有携带H889(SCLC)或RS4;11(ALL)肿瘤的动物中在处理结束后可持续数周。类似处理携带H146 SCLC肿瘤的小鼠能在动物中诱导迅速消退。
实施例9:合成
可以通过使用或调适图1中显示的合成方案来制备此发明的化合物。
实施例10:模型化合物的生化和细胞活性
在一种体外测定法中对化合物评估对配体结合Bcl-2的抑制。在依照实施例1中描述的方法的一种直接结合测定法(用于测定对肽配体结合对Bcl同等型的抑制的一种均质测定法)中对化合物评估对Bcl-xL活性的抑制。对选择的化合物获得的EC50值在表2A和表2B中显示。
依照实施例2和3中描述的方法在人细胞中对化合物评估衰老细胞杀伤活性。细胞系是人支气管上皮(HBE)细胞,小气道上皮(SAE)细胞,和人视网膜微血管内皮(HRMEC)细胞。此类细胞类型分别以登录号CRL-2741,PCS-301-010,和PCS-1101-010自美国典型培养物保藏中心(ATCC)可得。
在三种不同细胞系中对选择的化合物获得的LD50值在表3A和表3B中显示。
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此公开中呈现的数个假说提供阅读者可理解本发明的各个方面的前提。提供这个前提是为了使阅读者丰富知识。本发明的实施不要求详细理解或应用假说。除非另有说明,此公开中呈现的假说的特征并不限制要求保护的发明的应用或实施。
例如,除非明确要求消除衰老细胞,可以使用化合物来治疗描述的状况,不管它们对衰老细胞的作用。虽然此公开中提到的许多衰老相关状况主要在老年患者中发生,但是衰老细胞的发生及它们介导的病理生理可源自其它事件,诸如照射,其它类型的组织损伤,其它类型的疾病,和遗传异常。可以对具有所述状况的任何年龄患者实施本发明,除非另有明确指示或要求。
还提供了关于本公开的化合物的作用机制的讨论以使阅读者丰富知识,并不暗示任何限制。除非另有说明,可以使用化合物来去除衰老或癌细胞或治疗要求保护的疾病状况,不管它们如何在靶细胞内或在所治疗的受试者中运转。
虽然此公开中提到的化合物和组合物在消除衰老细胞和治疗衰老相关状况和癌症的语境中是例示性的,但是可以出于任何合适目的制备本文中描述的新颖的化合物和它们的衍生物,包括但不限于实验室用途,治疗衰老相关状况,用作汽车润滑剂,和用于诊断。
虽然已经参考举例说明描述了本发明,但是可以做出改变和等同取代以适应特定背景或预期用途作为常规开发和优化且在本领域普通技术人员范围内,由此实现本发明的益处而不脱离权利要求和它们的等同的范围。可以将说明书中提出的发明的其它技术方面并入权利要求以提供另外的区别特征。
Claims (34)
3.权利要求1或权利要求2的化合物,其中X3是-SO2CF3。
4.权利要求1或权利要求2的化合物,其中X3是-SO2CH3。
5.权利要求1或权利要求2的化合物,其中X3是-NO2。
6.权利要求1至5任一项的化合物,其中X5是-F。
7.权利要求1至5任一项的化合物,其中X5是-H。
8.权利要求1至7任一项的化合物,其中R6是-OH。
11.权利要求1至10任一项的化合物,其中R6中的羟基基团是磷酸化的。
12.权利要求10的化合物,其中R6中的羟基基团是用-PO3H2磷酸化的。
13.权利要求1至10任一项的化合物,其中X3不是-SO2CF3,且R6中的羟基基团不是磷酸化的。
14.权利要求1至12任一项的化合物,其中X2中的羧基基团是磷酸化的。
15.权利要求1或权利要求2的化合物,其选自表1A中列出的化合物。
16.权利要求1或权利要求2的化合物,其选自下面:
(R)-5-(4-氯苯基)-1-异丙基-2-甲基-4-(3-(4-(4-((3-(甲基磺酰基)-4-((1-(苯基硫)-4-(4-(膦酰氧基)哌啶-1-基)丁烷-2-基)氨基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-1-异丙基-2-甲基-4-(3-(4-(4-((4-((1-(苯基硫)-4-(4-((膦酰氧基)甲基)哌啶-1-基)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-(4-(4-((4-((4-(4-羟基哌啶-1-基)-1-(苯基硫)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-(4-(4-((4-((4-(4-(羟基甲基)哌啶-1-基)-1-(苯基硫)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-1-异丙基-2-甲基-4-(3-(4-(4-((4-((1-(苯基硫)-4-(4-(膦酰氧基)哌啶-1-基)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1H-吡咯-3-羧酸
(R)-5-(4-氯苯基)-4-(3-(4-(4-((4-((4-羟基-1-(苯基硫)丁烷-2-基)氨基)-3-((三氟甲基)磺酰基)苯基)磺胺代)苯基)哌嗪-1-基)苯基)-1-异丙基-2-甲基-1H-吡咯-3-羧酸。
17.前述权利要求任一项的化合物,其具有促凋亡活性。
18.前述权利要求任一项的化合物,其与非衰老细胞相比特异性杀伤衰老细胞,所述衰老细胞定义为表达p16的非癌性细胞。
19.前述权利要求任一项的化合物,其与相同组织类型的非癌细胞相比特异性杀伤癌细胞。
20.前述权利要求任一项的化合物,其具有小于1nM的对Bcl-xL的IC50和/或小于10nM的对Bcl-2的IC50。
21.前述权利要求任一项的化合物,其具有小于1μM的对经照射IMR90细胞或HRMEC细胞的LD50。
22.前述权利要求任一项的化合物,其具有比对汇合的IMR90细胞或对增殖中的IRM90细胞要低至少3倍的对经照射IMR90细胞的LD50。
23.一种药学组合物,其在药学相容赋形剂中包含依照前述权利要求任一项的化合物。
24.一种自混合细胞群体或组织选择性去除衰老细胞和/或癌细胞的方法,其包含使细胞,细胞群体或组织与依照权利要求1至23任一项的化合物或组合物接触。
25.一种治疗受试者中的组织中的衰老相关状况的方法(其中该衰老相关状况特征在于是至少部分由衰老细胞引起或介导的,或特征在于与未受影响的组织相比在该组织中或周围具有过多的衰老细胞),该方法包含:
对有需要的受试者的组织施用有效自该组织选择性去除衰老细胞的一定量的依照权利要求1至23任一项的化合物或组合物,由此缓解或改善该受试者中的衰老相关状况的一种或多种体征或症状。
26.药学组合物的单位剂量,其包含:
一定量的抑制Bcl功能的化合物,配置成供在至少部分由衰老细胞引起或介导的衰老相关状况的治疗中使用,
其中该化合物是依照权利要求1至22任一项的化合物,
其中该组合物含有该化合物的配制剂,配置成用于施用于表现出该衰老相关状况的受试者中的靶组织,
其中该单位剂量中的该配制剂和该一定量的该化合物将该单位剂量配置成当作为单剂施用于该组织时有效选择性去除该受试者中的该组织中或周围的衰老细胞,由此降低该状况的一种或多种体征或症状的严重程度而不在该受试者中引起不良作用。
27.权利要求26的单位剂量,其与描述药物在治疗衰老细胞相关状况中的使用和护理益处的信息插页一起包装。
28.依照权利要求1至22任一项的化合物或依照权利要求23的药学组合物,供在自组织或混合细胞群体选择性消除衰老细胞中使用或供在治疗衰老相关状况中使用。
29.依照权利要求1至22任一项的化合物在制造用于治疗衰老相关状况的药物中的用途。
30.权利要求25至29任一项的方法,产品,或用途,其中该状况是骨关节炎。
31.权利要求25至29任一项的方法,产品,或用途,其中该状况是眼部状况。
32.权利要求25至29任一项的方法,产品,或用途,其中该状况是肺部状况。
33.一种治疗癌症的方法,其包含对有需要的受试者的组织施用有效选择性自该组织去除癌细胞的一定量的依照权利要求1至23任一项的化合物或组合物。
34.依照权利要求1至22任一项的化合物或依照权利要求23的药学组合物,供在自组织或混合细胞群体选择性消除癌细胞中使用或供在治疗癌症中使用。
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CA3215235A1 (en) | 2021-04-13 | 2022-10-20 | Sharon KLIER | Methods of treating retinal vasculopathies |
Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103562202A (zh) * | 2011-01-25 | 2014-02-05 | 密执安大学评议会 | Bcl-2/bcl-xl抑制剂和使用它们的治疗方法 |
CN105246882A (zh) * | 2013-01-16 | 2016-01-13 | 密执安大学评议会 | BCL-2/Bcl-xL抑制剂和使用所述抑制剂的治疗方法 |
CN108025006A (zh) * | 2015-02-06 | 2018-05-11 | 尤尼蒂生物技术公司 | 化合物及在治疗衰老相关病症中的用途 |
Family Cites Families (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP1685140A4 (en) * | 2003-11-18 | 2009-02-25 | Novogen Res Pty Ltd | PRODRUGS BASED ON ISOFLAVONOIDS, COMPOSITIONS THEREOF AND THERAPEUTIC PROCESSES INVOLVING THEM |
US8563735B2 (en) | 2008-12-05 | 2013-10-22 | Abbvie Inc. | Bcl-2-selective apoptosis-inducing agents for the treatment of cancer and immune diseases |
US9006284B2 (en) * | 2009-08-27 | 2015-04-14 | Bionomics Limited | Combination therapy for treating proliferative diseases |
TWI535712B (zh) | 2010-08-06 | 2016-06-01 | 阿斯特捷利康公司 | 化合物 |
WO2012177927A1 (en) | 2011-06-21 | 2012-12-27 | Mayo Foundation For Medical Education And Research | Transgenic animals capable of being induced to delete senescent cells |
US9901080B2 (en) | 2012-08-23 | 2018-02-27 | Buck Institute For Research On Aging | Transgenic mouse having a transgene that converts a prodrug into a cytotoxic compound in senescent cells |
US20160038503A1 (en) | 2012-11-21 | 2016-02-11 | David Richard | Methods and compositions useful for treating diseases involving bcl-2 family proteins with isoquinoline and quinoline derivatives |
BR112015026702A2 (pt) | 2013-04-21 | 2018-02-06 | Yeda Res And Developmente Co Ltd | métodos de extermínio de células senescentes |
SG10201805670QA (en) | 2014-01-28 | 2018-08-30 | Buck Inst Res Aging | Methods and compositions for killing senescent cells and for treating senescence-associated diseases and disorders |
WO2015116735A1 (en) | 2014-01-28 | 2015-08-06 | Mayo Foundation For Medical Education And Research | Methods and combinations for killing senescent cells and for treating senescence-associated diseases and disorders |
EP3139942B1 (en) | 2014-05-05 | 2019-12-18 | Bioventures, Llc | COMPOSITIONS AND METHODS FOR INHIBITING ANTIAPOPTOTIC Bcl-2 PROTEINS AS ANTI-AGING AGENTS |
US20180000816A1 (en) | 2015-02-06 | 2018-01-04 | Unity Biotechnology, Inc. | Use of a Heterocyclic Bcl-xL Inhibitor and Related Analogs for Removing Senescent Cells in the Treatment of Eye Diseases and Other Age-Related Conditions |
US10195213B2 (en) | 2015-03-13 | 2019-02-05 | Unity Biotechnology, Inc. | Chemical entities that kill senescent cells for use in treating age-related disease |
WO2016185481A2 (en) | 2015-05-20 | 2016-11-24 | Yeda Research And Development Co. Ltd. | Method of targeting senescent cells |
WO2019033122A1 (en) * | 2017-08-11 | 2019-02-14 | Unity Biotechnology, Inc. | TREATMENT OF PULMONARY DISEASES USING PHARMACEUTICAL AGENTS THAT ELIMINATE SENESCENT CELLS |
EP3441069B1 (en) | 2017-08-11 | 2023-04-05 | Unity Biotechnology, Inc. | Treatment of diabetic retinopathy using pharmaceutical agents that eliminate senescent cells |
US10588916B2 (en) | 2017-10-31 | 2020-03-17 | Unity Biotechnology, Inc. | Technology to inhibit vascular changes that lead to vision loss in the eye |
-
2018
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
CN103562202A (zh) * | 2011-01-25 | 2014-02-05 | 密执安大学评议会 | Bcl-2/bcl-xl抑制剂和使用它们的治疗方法 |
CN105246882A (zh) * | 2013-01-16 | 2016-01-13 | 密执安大学评议会 | BCL-2/Bcl-xL抑制剂和使用所述抑制剂的治疗方法 |
CN108025006A (zh) * | 2015-02-06 | 2018-05-11 | 尤尼蒂生物技术公司 | 化合物及在治疗衰老相关病症中的用途 |
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