CN110769853A - 治疗雄性衰老 - Google Patents
治疗雄性衰老 Download PDFInfo
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- CN110769853A CN110769853A CN201880040019.5A CN201880040019A CN110769853A CN 110769853 A CN110769853 A CN 110769853A CN 201880040019 A CN201880040019 A CN 201880040019A CN 110769853 A CN110769853 A CN 110769853A
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- methyl
- dimethyl
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- dione
- phenyl
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- 238000000034 method Methods 0.000 claims abstract description 26
- 102100022501 Receptor-interacting serine/threonine-protein kinase 1 Human genes 0.000 claims abstract description 21
- 101001109145 Homo sapiens Receptor-interacting serine/threonine-protein kinase 1 Proteins 0.000 claims abstract description 19
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Abstract
本发明提供了治疗雄性生殖衰老的方法,该方法包括向有其需要的雄性给予包括RIP1、RIP3或MLKL的抑制剂的坏死性凋亡抑制剂。本发明还提供了药物组合物,所述药物组合物包含坏死性凋亡抑制剂和用于治疗雄性衰老的第二种不同的药物。
Description
介绍
坏死性凋亡是由细胞因子的肿瘤坏死因子家族引起的程序性坏死性细胞死亡的形式(Christofferson和Yuan,2010;Vandenabeele等人,2010)。响应TNF受体家族成员的激活,受体相互作用激酶1(RIP1)被募集到受体的胞质侧,并且其激酶活性被激活(Holler等人,2000)。然后,RIP1与相关的激酶RIP3相互作用并使其磷酸化,导致其活化(Cho等人,2009;Degterev等人,2008;He等人,2009;Zhang等人,2009)。如果细胞的胱天蛋白酶-8活性也碰巧通过与其细胞抑制剂cFLIP相互作用或通过病毒或化学抑制剂的作用被抑制,则RIP3驱动细胞命运走向坏死性凋亡(He等人,2009;Holler等人,2000)。坏死性凋亡可以被RIP1激酶抑制剂化合物抑制,并且可以被小分子Smac模拟物促进,使RIP1功能从NF-κB激活转变为RIP3的激活(Degterev等人,2008;Wang等人,2008)。一旦激活,RIP3就使一种称为混合谱系激酶结构域样蛋白(MLKL)的假激酶磷酸化(Sun等人,2012)。MLKL通常以非活性单体形式存在于细胞质中。在人MLKL的丝氨酸357和苏氨酸358或小鼠的等价的丝氨酸345、丝氨酸347和苏氨酸349上RIP3磷酸化后,MLKL形成寡聚物并转移至质膜,其在质膜处破坏膜完整性,导致坏死性细胞死亡(Cai等人,2014;Chen等人,2014;Rodriguez等人,2016;Sun等人,2012;Wang等人,2014)。
由于RIP3敲除小鼠在防御微生物感染中表现出缺陷或在多种化学或缺血性再灌注诱导的组织损伤模型中显现出较少的组织损伤,因此知道坏死性凋亡在微生物感染或组织损伤的病理条件下具有重要的功能(Cho等人,2009;He等人,2009;Robinson等人,2012;Upton等人,2010;Zhou和Yuan,2014)。然而,如果不受微生物感染或组织破坏剂的刺激,RIP3或MLKL基因敲除的小鼠则非常正常,没有任何明显的发育或生育能力缺陷(Murphy等人,2013;Newton等人,2004;Wu等人,2013)。
在进行考察坏死性凋亡对动脉粥样硬化进展的影响的研究(Meng等人,2015)时,我们偶然发现RIP3和MLKL敲除的小鼠的雄性生殖器官即使在老年时也看起来非常年轻。我们在这里呈现的全面的追踪工作表明,坏死性凋亡在促进小鼠雄性生殖系统衰老中起作用,为治疗和预防干预提供了靶标。
发明概述
本发明提供了用于治疗雄性衰老或其症状或指标的方法和组合物。一方面,本发明提供了一种治疗雄性衰老的方法,其包括向有其需要的雄性给予坏死性凋亡抑制剂。
在实施方案中:
坏死性凋亡抑制剂是RIP1、RIP3或MLKL抑制剂。
坏死性凋亡抑制剂是选自以下的RIP1抑制剂:
5-((1H-吲哚-3-基)甲基)-3-甲基-2-硫代咪唑烷-4-酮(Nec-1);
(S)-苯基(5-苯基-4,5-二氢-1H-吡唑-1-基)甲酮;
5-((1H-吲哚-3-基)甲基)-3-甲基-2-硫代咪唑烷-4-酮(Nec-1s);
3-甲基-5-((7-甲基-1H-吲哚-3-基)甲基)咪唑烷-2,4-二酮;
(R)-5-((7-氯-1H-吲哚-3-基)甲基)-3-甲基咪唑烷-2,4-二酮;
(R)-5-((7-氯-1H-吲哚-3-基)甲基)-3-(4-(3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯基)丁基)咪唑烷-2,4-二酮(帕纳替尼-Nec 1s);
(S)-2,2-二甲基-1-(5-苯基-4,5-二氢-1H-吡唑-1-基)丙-1-酮(GSK963);
(S)-2,2-二甲基-1-(5-苯基-4,5-二氢-1H-吡唑-1-基)丙-1-酮;
(S)-1-(4-(5-苯基-4,5-二氢-1H-吡唑-1-羰基)哌啶-1-基)乙酮;
(S)-2,2-二甲基-1-(5-(吡啶-2-基)-4,5-二氢-1H-吡唑-1-基)丙-1-酮;
(S)-1-(4-(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-羰基)哌啶-1-基)乙酮;
1-(4-(4-氨基呋喃并[2,3-d]嘧啶-5-基)苯基)-3-(2-氟-5-(三氟甲基)苯基)脲(Cpd27);
3-甲基-5-((7-甲基-1H-吲哚-3-基)甲基)咪唑烷-2,4-二酮;
(R)-5-((7-氯-1H-吲哚-3-基)甲基)-3-甲基咪唑烷-2,4-二酮;
3-苄基-6,7-二氢-3H-环戊烷并[4,5]噻吩并[2,3-d]嘧啶-4(5H)-酮;
N-(3-氯-2,6-二氟苄基)-4-环丙基-1,2,3-噻二唑-5-甲酰胺;
(S)-N-(1-(2-氯-6-氟苯基)乙基)-5-氰基-1-甲基-1H-吡咯-2-甲酰胺;
(S)-N-(1-(2-氯-6-氟苯基)乙基)-4-环丙基-1,2,3-噻二唑-5-甲酰胺;
N-苄基-N-羟基-2,2-二甲基丁酰胺;
N-(4-氟苄基)-N-羟基-2,2-二甲基丁酰胺;
N-(2,4-二氟苄基)-N-羟基-2,2-二甲基丁酰胺;
N-(3,4-二氟苄基)-N-羟基-2,2-二甲基丁酰胺;
N-羟基-2,2-二甲基-N-(2,3,4-三氟苄基)丁酰胺;
N-羟基-2,2-二甲基-N-(3,4,5-三氟苄基)丁酰胺;
N-羟基-2,2-二甲基-N-(2,3,5-三氟苄基)丁酰胺;
(2-(3-氟苯基)吡咯烷-1-基)(1-(三氟甲基)环戊基)甲酮;
(2-(3-氟苯基)吡咯烷-1-基)(1-(三氟甲基)环丁基)甲酮;
(S)-1-(2,2-二甲基丁-3-烯酰基)-4-苯基氮杂环丁-2-酮;
(S)-2,2-二甲基-1-(2-苯基氮杂环丁-1-基)丁-3-炔-1-酮;和
(S)-1-(2,2-二甲基丁酰基)-4-苯基氮杂环丁-2-酮;
或WO2016/101885或WO2016/101887中公开的RIP1抑制剂;
坏死性凋亡抑制剂是选自以下的RIP3抑制剂:
2-(4-(5-(甲基氨基甲酰基)-1H-苯并[d]咪唑-1-基)苯基)乙酸叔丁酯(GSK'840);
3-(苯并[d]噻唑-5-基)-7-(1,3-二甲基-1H-吡唑-5-基)噻吩并[3,2-c]吡啶-4-胺(GSK'843);
N-(6-(异丙基磺酰基)喹啉-4-基)苯并[d]噻唑-5-胺(GSK'872);
N-[3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-4-噻唑基]-2-氟苯基]-2,6-二氟-苯磺酰胺(达拉菲尼);
3-(2-咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基-N-[4-[(4-甲基-1-哌嗪基)甲基]-3-(三氟甲基)苯基]-苯甲酰胺(帕纳替尼);和
5-[[4-[(2,3-二甲基-2H-吲唑-6-基)甲基氨基]-2-嘧啶基]氨基]-2-甲基-苯磺酰胺(帕唑帕尼);
坏死性凋亡抑制剂是选自以下的MLKL抑制剂:
(2E)-N-[4-[[(3-甲氧基-2-吡嗪基)氨基]磺酰基]苯基]-3-(5-硝基-2-噻吩基)-2-丙烯酰胺(Necrosulfonamide);
1,3,7-三甲基-8-(甲基磺酰基)-1H-嘌呤-2,6(3H,7H)-二酮(TC13-4);
8-(2,5-二甲氧基苄基磺酰基)-1,3,7-三甲基-1H-嘌呤-2,6(3H,7H)-二酮(TC13-58);
7-乙基-1,3-二甲基-8-(甲基磺酰基)-1H-嘌呤-2,6(3H,7H)-二酮(TC13-74);
1,7-二甲基-8-(甲基磺酰基)-3-(丙-2-炔基)-1H-嘌呤-2,6(3H,7H)-二酮(TC13-106);
2-(1,7-二甲基-8-(甲基磺酰基)-2,6-二氧代-1H-嘌呤-3(2H,6H,7H)-基)乙腈(TC13-107);
3-(3-(3-氯苯基)丙-2-炔-1-基)-8-((环丙基甲基)磺酰基)-1,7-二甲基-3,7-二氢-1H-嘌呤-2,6-二酮(TC13-119);
8-((2,5-二甲氧基苄基)磺酰基)-1,7-二甲基-3-(3-(2-(甲基氨基)吡啶-4-基)丙-2-炔-1-基)-3,7-二氢-1H-嘌呤-2,6-二酮(TC13-127);
3-(3-(3-羟基苯基)丙-2-炔-1-基)-1,7-二甲基-8-(甲基磺酰基)-3,7-二氢-1H-嘌呤-2,6-二酮(TC13-172);和
3-((4-(甲基(4-(3-(4-(三氟甲氧基)苯基)脲基)苯基)氨基)嘧啶-2-基)氨基)苯磺酰胺(化合物1);或
PCT/CN2018/077464中公开的MLKL抑制剂;
所述雄性衰老选自与年龄相关的低睾酮、低性欲、勃起功能障碍、体重增加、肌肉质量或肌张力降低和前列腺增生;
所述方法还包括向雄性给予用于治疗雄性衰老的第二种不同的药物;和/或
所述方法还包括诊断雄性衰老的先前步骤,和/或检测得到的雄性衰老的减轻或逆转的后续步骤。
在其他方面,本发明提供了一种药物组合物,其包含坏死性凋亡抑制剂和用于治疗雄性衰老的第二种不同的药物。
在实施方案中:
所述不同的药物选自雄激素,包括外源性和内源性同化雄性类固醇、内源性雄激素刺激剂(例如,顺式克罗米酚、克罗米酚)、雌激素抑制剂(例如,抗雌激素剂,如克罗米酚、反式克罗米酚、他莫昔芬、雷洛昔芬)、生长激素(例如,HGH);
所述不同的药物选自:
睾酮、普拉睾酮(去氢表雄酮、DHEA)、雄烯二酮(A4)、雄烯二醇(A5)、二氢睾酮(DHT)、1-雄烯二醇、1-雄烯二酮、勃雄二醇、勃拉睾酮、勃地酮、勃二酮、卡普睾酮、氯睾酮、达那唑、脱氢氯甲基睾酮、去氧甲基睾酮、屈他雄酮、乙雌烯醇、氟甲睾酮、甲酰勃龙、夫拉扎勃、孕三烯酮、4-羟基睾酮、美雄诺龙、美睾酮、美替诺龙、去氢甲睾酮、美雄醇、甲基屈他雄酮、甲二烯诺龙、甲基-1-睾酮、甲基去甲睾酮、甲基睾酮、美曲勃龙、米勃龙、诺龙、19-去甲雄烯二酮、诺勃酮、诺司替勃、诺乙雄龙、羟勃龙、氧雄龙、羟甲睾酮、羟甲烯龙、普罗斯它诺唑、奎勃龙、司坦唑醇、司腾勃龙、1-睾酮、四氢孕三烯酮和群勃龙;和/或
所述组合物为单位剂型。
本发明包括本文叙述的特定实施方案的所有组合。
本发明的特定实施方案的描述
以举例说明的方式而非以限制的方式提供以下对特定实施方案和实施例的描述。本领域技术人员将容易地认识到可以改变或修改各个非关键参数以产生基本相似的结果。本发明提供了多种实施方案。
除非另有相反的提示或注明,在这些描述和整个说明书中,术语“一(a)”和“一(an)”意指一个或多个,术语“或”意指和/或,并且多核苷酸序列被理解为包括相反链以及本文所述的供选择的骨架。
本发明提供了用于治疗雄性衰老的方法和组合物,所述雄性衰老特别是生殖(生育能力和/或生殖力)衰老或其症状或指标,例如与年龄相关的低睾酮、低性欲、勃起功能障碍、体重增加、肌肉质量或肌张力降低和前列腺增生。一方面,本发明提供了一种治疗雄性衰老的方法,该方法包括向有其需要的雄性给予坏死性凋亡抑制剂,特别是RIP1、RIP3或MLKL抑制剂。合适的RIP1、RIP3和MLKL抑制剂是本领域已知的,由以下参考文献和代表性抑制剂证明:
所述方法和组合物可以采用任何合适的形式和剂量单位的化合物,包括盐、前药、立体异构体、无定形形式等。
术语“药学上可接受的盐”意在包括根据在本文所述的化合物上存在的具体取代基,用相对无毒的酸或碱制备的活性化合物的盐。当本发明的化合物含有相对酸性的官能团时,可以通过使这样的化合物的中性形式与足量的期望的碱(纯的或在合适的惰性溶剂中)接触来获得碱加成盐。药学上可接受的碱加成盐的实例包括钠、钾、钙、铵、有机胺或镁盐,或类似的盐。当本发明的化合物含有相对碱性的官能团时,可以通过将这样的化合物的中性形式与足量的期望的酸(纯的或在合适的惰性溶剂中)接触来获得酸加成盐。药学上可接受的酸加成盐的实例包括衍生自无机酸,如盐酸、氢溴酸、硝酸、碳酸、一氢碳酸、磷酸、一氢磷酸、二氢磷酸、硫酸、一氢硫酸、氢碘酸或亚磷酸等的那些,以及衍生自相对无毒的有机酸,如乙酸、丙酸、异丁酸、草酸、马来酸、丙二酸、苯甲酸、琥珀酸、辛二酸、富马酸、扁桃酸、邻苯二甲酸、苯磺酸、对甲苯磺酸、柠檬酸、酒石酸,甲磺酸等的盐。还包括氨基酸,例如精氨酸等的盐,以及有机酸,如葡糖醛酸或半乳糖醛酸等的盐。本发明的某些特定化合物同时含有碱性和酸性官能团,其允许化合物转化为碱或酸加成盐。
化合物的中性形式可以通过使盐与碱或酸接触并以常规方式分离母体化合物来再生成。化合物的母体形式在某些物理特性,例如极性溶剂中的溶解度方面,不同于各种盐的形式,但是在别的方面对于本发明的目的而言,盐等同于化合物的母体形式。
除了盐形式之外,本发明提供了前药形式的化合物。本文所述的化合物的前药是在生理条件下经过化学变化以提供本发明化合物的那些化合物。另外,前药可以在离体环境中通过化学或生物化学方法转化为本发明的化合物。例如,当与合适的酶或化学试剂共同置于透皮贴剂储库中时,前药可被缓慢转化为本发明的化合物。前药经常是有用的,因为在一些情况下,它们可能比母体药物更容易给予。例如,它们可能比母体药物口服生物利用度更高。前药在药物组合物中也可能有相对于母体药物改善的溶解性。本领域已知各种各样的前药衍生物,例如依赖于前药的水解裂解或氧化活化的那些。前药的非限制性实例是作为酯(“前药”)给予,但随后被代谢水解成羧酸,即活性实体的本发明的化合物。另外的实例包括本发明的化合物的肽基衍生物。
本发明的某些化合物可以非溶剂化形式以及溶剂化形式存在,包括水合物形式。通常,溶剂化形式等同于非溶剂化形式,并且意图包括在本发明的范围内。本发明的某些化合物可以以多种结晶或无定形形式存在。通常,所有物理形式对于本发明所考虑的用途是等效的,并且意图在本发明的范围内。
本发明的某些化合物具有不对称碳原子(光学中心)或双键;外消旋体、非对映异构体、几何异构体和单个异构体都意图包括在本发明的范围内。
术语“治疗有效量”是指研究者、兽医、医生或其他临床医生所寻求的,例如当给予时,将在一定明显程度上引起组织、系统、动物或人的生物或医学反应的主题化合物的量,其足以预防所处理的病症或障碍的一种或多种症状的发展或在一定程度上减轻所处理的病症或障碍的一种或多种症状。治疗有效量会根据化合物、疾病及其严重程度,以及待治疗的哺乳动物的年龄、体重等变化。
本发明还提供了包含主题化合物和药学上可接受的赋形剂的药物组合物,特别是包含单位剂量的主题化合物的这样的组合物,特别是与描述该组合物用于治疗可适用的疾病或病症(本文中)的说明书共包装的这样的组合物。
用于给予的组合物可以采取散装液体溶液或悬浮液或散装粉末的形式。然而,更普遍地,该组合物以单位剂型呈现以促进精确给药。术语“单位剂型”是指适合作为人类受试者和其它哺乳动物的单位剂量的物理上离散的单位,每个单位含有计算产生期望治疗效果的预定量的活性物质,并与合适的药物赋形剂结合。典型的单位剂型包括液体组合物的预先填充的、预先计量的安瓿或注射器,或在固体组合物的情况下的丸剂、片剂、胶囊、锭剂等。在这样的组合物中,化合物通常是少量组分(约从0.1%至约50%重量,或优选地约为1%至40%重量),其余是有助于形成期望给药形式的各种溶媒或载体和加工助剂。
合适的赋形剂或载体和用于制备可给予的组合物的方法是本领域技术人员已知或显而易见的,并且在诸如Remington's Pharmaceutical Science,Mack Publishing Co,NJ(1991)的出版物中有更详细的描述。此外,化合物可有利地与本文所述的或本领域另外已知的其它治疗剂,特别是其它抗坏死剂联合使用。因此,组合物可以以单一剂量单位单独、联合或组合给予。
给予量取决于化合物剂型、给予途径等,并且通常在常规试验中凭经验确定,并且根据靶标、宿主和给予途径等将必然发生变化。通常,根据具体应用,单位剂量制剂中活性化合物的量可以从约1、3、10或30到约30、100、300或1000mg变化或调节。在一个具体实施方案中,单位剂型包装在适于顺序使用的多包装中,例如包括至少6、9或12个单位剂型的片的泡罩包装。所用的实际剂量可以根据患者的需要和所治疗的病症的严重程度而变化。确定对于特定情况的适当剂量在本领域的技术范围内。通常,用小于化合物的最佳剂量的较小剂量开始治疗。此后,剂量少量增加,直到达到在所述情况下的最佳效果。为了方便起见,如果需要,总日剂量可以分开并在当天内按份给予。
化合物可以通过各种方法给予,包括但不限于胃肠外、局部(topical)、口服或局部(local)给予,例如通过气雾剂或经皮,用于预防性和/或治疗性处理。此外,根据熟练临床医生的知识,治疗方案(例如,给予的剂量和次数)可以视所观察到的给予的治疗剂对患者的作用及视所观察到的疾病对所给予的治疗剂的反应而变化。
在用于治疗患者的治疗有效方案的过程中,可以以治疗有效剂量和量给予本发明的治疗剂。对于更有效的化合物,每千克患者的微克(ug)量可能是足够的,例如在约1、10或100ug/kg至约0.01、0.1、1、10或100mg/kg的患者体重范围内,尽管最佳剂量是化合物特异性的,并且通常对于每种化合物是凭经验确定的。
一般来说,临床试验中的常规实验将确定最佳治疗效果的具体范围,对于每种治疗剂,每种给予方案以及对特定患者的给予也将根据患者状况和对初始给予的反应被调整到有效和安全的范围内。然而,最终给予方案将根据主治临床医生的判断,考虑诸如年龄、病人的状况和体型以及化合物效力、所治疗疾病的严重程度等因素来调整。例如,化合物的剂量方案可以是以两至四个(优选两个)分开的剂量口服给予10毫克至2000毫克/天,优选10至1000毫克/天,更优选50至600毫克/天。还可以使用间歇治疗(例如,三周中的一周或四周中的三周)。
主题化合物可以单独使用或与其他治疗剂组合使用。因此,组合疗法包括给予化合物的至少一种药学上可接受的结晶或无定形形式和至少一种其他治疗活性剂。主题化合物和(多种)其他治疗活性剂可以在单一药物组合物中一起给予或分开给予,并且当分开给予时,这可以同时或以任何顺序依次发生。选择主题化合物和(多种)其他治疗活性剂的量以及给予的相对时机,以获得期望的联合治疗效果。因此,另一方面,提供了包含化合物的药学上可接受的结晶或无定形形式以及一种或多种其他治疗活性剂的组合。
本发明的化合物可以通过任何合适的给予途径给予,包括全身给予和局部给予。全身给予包括口服给予、肠胃外给予、经皮给予、直肠给予和通过吸入给予。肠胃外给予是指除肠内、经皮或通过吸入以外的给予途径,并且通常通过注射或输注进行。肠胃外给予包括静脉内、肌内和皮下注射或输注。吸入是指通过口腔或通过鼻道吸入给予到患者的肺里。局部给予包括施加到皮肤。
本发明的化合物可以一次给予或根据给药方案给予,其中在给定的时间段内以不同的时间间隔给予多个剂量。例如,可以每天一次、两次、三次或四次给药。可以给药直至达到期望的治疗效果或无限期地维持期望的治疗效果。适合本发明的化合物的给药方案取决于该化合物的药代动力学性质,例如吸收、分布和半衰期,其可以由技术人员确定。另外,对于本发明的化合物,合适的给药方案,包括施用这种方案的持续时间,取决于所治疗的疾病或障碍、所治疗的疾病或障碍的严重程度、所治疗的患者的年龄和身体状况、所治疗的患者的病史、同时进行的治疗的性质、期望的治疗效果以及技术人员的知识和专业内的类似因素。这样的技术人员将进一步懂得,鉴于个体患者对给予方案的反应或个体患者随着时间推移的需求的变化,可能需要调整合适的给药方案。每日总剂量为1mg至2000mg。
对于在治疗中的使用,在向患者给予之前,通常但并非必须将本发明的化合物配制成药物组合物或给药单位。因此,本发明还涉及包含本发明的化合物和一种或多种药学上可接受的赋形剂的药物组合物。本发明还涉及包含本发明的化合物和一种或多种药学上可接受的赋形剂的给药单位。
本发明的药物组合物或给药单位可以以散装形式制备和包装,其中可以提取有效量的本发明的化合物,然后例如与粉末、糖浆和注射液一起给予患者。供选择地,可以制备本发明的药物组合物或给药单位并包装成单位剂型。对于口服应用,例如,可以给予一种或多种片剂或胶囊剂。一剂药物组合物包含至少治疗有效量的本发明的化合物。当以单位剂型制备时,药物组合物或给药单位可以包含1mg至1000mg的主题化合物。
如本文所提供的,含有1mg至1000mg化合物的单位剂型(药物组合物或给药单位)可以每天给予1、2、3或4次,优选每天1、2或3次,更优选每天一次或两次。
如本文所使用的,“药学上可接受的赋形剂”意指涉及赋予组合物形状或稠度的材料、组合物或溶媒。每种赋形剂当混合时必须与药物组合物的其他成分相容,从而避免了在给予患者时会大大降低本发明的化合物的功效的相互作用,以及会导致药物组合物在药学上不可接受的相互作用。另外,每种赋形剂当然必须具有足够高的纯度以使其是药学上可接受的。
本发明的化合物和药学上可接受的赋形剂或多种赋形剂通常配制成适于通过期望的给予途径向患者给予的剂型。常规剂型包括:(1)适于口服给予的剂型,例如片剂、胶囊剂、囊片、丸剂、锭剂、散剂、糖浆剂、酏剂、混悬剂、溶液剂、乳剂、囊袋剂和扁囊剂;(2)适于肠胃外给予的剂型,如无菌溶液、混悬剂和用于重构的粉末等;(3)适于透皮给予的剂型,例如透皮贴剂;(4)适于直肠给予的剂型,如栓剂;(5)适于吸入的剂型,例如气雾剂和溶液;和(6)适于局部给予的剂型,例如乳膏剂、软膏剂、洗剂、溶液剂、糊剂、喷雾剂、泡沫剂和凝胶剂。
适合的药学上可接受的赋形剂将根据所选的特定剂型而变化。另外,可以针对它们可以在组合物中发挥的特定功能选择合适的药学上可接受的赋形剂。例如,可以选择某些药学上可接受的赋形剂,因为它们能够促进均匀剂型的生产。可以选择某些药学上可接受的赋形剂,因为它们能够促进稳定剂型的生产。可以选择某些药学上可接受的赋形剂,因为它们一旦向患者给予就能够促进将本发明的一种或多种化合物从一个器官或身体的一部分携带或运送到另一器官或身体的另一部分。可以选择某些药学上可接受的赋形剂,因为它们能够提高患者依从性。
适合的药学上可接受的赋形剂包括以下类型的赋形剂:稀释剂、填充剂、粘合剂、崩解剂、润滑剂、助流剂、制粒剂、包衣剂、润湿剂、溶剂、共溶剂、助悬剂、乳化剂、甜味剂、调味剂、掩味剂、着色剂、抗结块剂、保湿剂、螯合剂、增塑剂、增粘剂、抗氧化剂、防腐剂、稳定剂、表面活性剂和缓冲剂。本领域技术人员将理解,根据制剂中存在的赋形剂的量和制剂中存在的其他成分的种类,某些药学上可接受的赋形剂可以起到一种以上的功能并且可以起到供选择的功能。技术人员具有本领域的知识和技能,以使他们能够选择用于本发明的合适量的合适的药学上可接受的赋形剂。另外,本领域技术人员可获得许多描述药学上可接受的赋形剂的资源,这些资源可用于选择合适的药学上可接受的赋形剂。实例包括雷明顿制药科学(Remington's Pharmaceutical Sciences,Mack Publishing Company)、药物添加剂手册(The Handbook of Pharmaceutical Additives,Gower Publishing Limited)和药物赋形剂手册(The Handbook of Pharmaceutical Excipients,the AmericanPharmaceutical Association and the Pharmaceutical Press)。
使用本领域技术人员已知的技术和方法制备本发明的药物组合物。雷明顿制药科学(同上)中描述了本领域中常用的一些方法。因此,本发明的另一个实施方案是制备药物组合物或给药单位的方法,该方法包括将主题化合物的药学上可接受的晶体与一种或多种药学上可接受的赋形剂混合的步骤。
一方面,本发明涉及固体口服剂型,例如片剂或胶囊剂,其包含有效量的本发明的化合物和稀释剂或填充剂。合适的稀释剂和填充剂包括乳糖、蔗糖、右旋糖、甘露醇、山梨糖醇、淀粉(例如玉米淀粉、马铃薯淀粉和预胶化淀粉)、纤维素及其衍生物(例如微晶纤维素)、硫酸钙和磷酸氢钙。口服固体剂型可进一步包含粘合剂。合适的粘合剂包括淀粉(例如玉米淀粉、马铃薯淀粉和预胶化淀粉)、明胶、阿拉伯胶、海藻酸钠、海藻酸、黄蓍胶、瓜尔豆胶、聚维酮和纤维素及其衍生物(例如微晶纤维素)。口服固体剂型可以进一步包含崩解剂。合适的崩解剂包括交聚维酮、羟乙酸淀粉钠、交联羧甲纤维素钠、海藻酸和羧甲基纤维素钠。口服固体剂型可以进一步包含润滑剂。合适的润滑剂包括硬脂酸、硬脂酸镁、硬脂酸钙和滑石。
应理解,本文所述的实施例和实施方案仅用于说明目的,并且本领域技术人员鉴于其会联想到各种修改或变化,而且各种修改或变化包括在本申请的精神和范围以及所附权利要求的范围内。本文引用的所有出版物、专利和专利申请(包括其中的引用)出于所有目的在此整体通过引用并入。
实施例
RIP3敲除小鼠中生殖器官的衰老被延迟
我们首先注意到C57BL/6品系的18月龄的RIP3敲除(RIP3-/-)小鼠看起来比在相同条件下饲养的相同品系的同龄野生型(WT,RIP3+/+)小鼠瘦。18月龄野生型小鼠平均重量为46克,显著高于同龄RIP3敲除小鼠的37克的重量。另一方面,4月龄野生型和RIP3敲除小鼠的重量是无法区分的。除了整个体重的差异外,精囊(小鼠雄性生殖系统中的辅助腺)在18月龄RIP3敲除小鼠和野生型小鼠之间似乎也有很大差异。来自18月龄野生型小鼠(n=33)的精囊重量为~1,000mg至4,500mg,而来自同龄RIP3敲除小鼠(n=30)的相同器官的重量大多在1,000mg以下。
已知的是,随着小鼠变老,精囊变大(Finch和Girgis,1974;Pettan-Brewer和Truting,2011)。来自野生型小鼠和RIP3敲除小鼠的精囊的差异在存活一年后就变得明显,并且随着时间的推移变得越来越明显。来自野生型小鼠的精囊继续生长,而来自RIP3敲除小鼠的精囊在4个月至24个月尺寸没有变化。在野生型小鼠和RIP3敲除小鼠之间,精囊的整体解剖结构没有明显差异。仔细检查发现,来自18月龄野生型小鼠的精囊上皮显示出不规则性,上皮和液体区室(liquid compartment)被空间分隔开,而同龄RIP3敲除小鼠的精囊上皮细胞紧密堆积,就像它们在幼龄小鼠中一样。
小鼠的精囊在解剖学上是简单的,仅由包裹液体区室的上皮层组成(Gonzales,2001)。因此,野生型小鼠和RIP3敲除小鼠之间的精囊差异并不能提供导致这种表型的很多机理性见解。我们进一步研究了野生型小鼠和RIP3敲除小鼠的睾丸。当小鼠达到18月龄时,野生型睾丸开始出现萎缩,并且重量小于RIP3敲除睾丸。一致地是,随着野生型小鼠从4月龄到18月龄,睾酮水平显现出急剧下降,而在同一时期,RIP3基因敲除小鼠的睾酮水平几乎没有下降。此外,在RIP3敲除小鼠中未观察到已知在野生型小鼠中发生的典型的性激素结合球蛋白(SHBG)的与年龄相关的增加(Vermeulen等人,1996)。有趣的是,脑垂体分泌的两种内分泌因子LH和FSH的水平(Cooke和Saunders,2002)在野生型小鼠和RIP3敲除小鼠之间没有差异;当小鼠从4月龄到18月龄时,两者均显著下降。这一发现表明,老龄野生型小鼠和RIP3敲除小鼠之间生殖系统衰老的差异可能是睾丸局部改变所致。
与人类在生殖器官衰老时常发生的情况不同,小鼠前列腺的苏木精和伊红(H&E)染色显示野生型或RIP3敲除基因型的幼龄(4月龄)或老龄(18月龄)小鼠的前侧、背侧、腹侧或外侧前列腺切片无明显的解剖学差异(Pettan-Brewer和Treuting,2011)。
RIP3的敲除防止衰老的睾丸中曲精小管中细胞的消耗
当雄性小鼠性成熟时,其睾丸中曲精小管的中央管腔开始充满由周围精原干细胞产生的精子。精原干细胞和精母细胞由塞尔托利氏细胞支持,所述塞尔托利氏细胞为精子发生提供营养因子和结构支持(Cooke和Saunders,2002)。然后精子转移并储存在附睾中,从附睾中排出成熟精子。与来自精囊和前列腺的液体混合后,精子独自移动通过射精道,在其中形成精液(Cooke和Saunders,2002)。
当解剖来自4月龄和18月龄野生型小鼠和RIP3敲除小鼠的睾丸并在显微镜下检查它们的横截面时,来自18月龄野生型小鼠的许多曲精小管中的细胞丧失,使曲精小管呈现“空”的外观。相比之下,4月龄野生型小鼠和RIP3敲除小鼠的曲精小管的中心管腔被细胞完全包围,并充满了精子。引人注目的是,18月龄RIP3敲除小鼠的曲精小管看起来与4月龄小鼠的曲精小管没有区别。更为显著的是,当检查36月龄小鼠的睾丸切片时,野生型小鼠的接近一半的曲精小管是空的,而来自RIP3敲除小鼠的多于90%的曲精小管看起来仍是正常的。
来自曲精小管的精子移动到附睾,在那里它们成熟并在射精之前被储存(Cooke和Saunders,2002)。与在曲精小管中观察到的表型相似,大多数来自18月龄野生型小鼠的附睾中几乎没有精子,而大多数同龄RIP3敲除小鼠的附睾中则充满了精子。附睾中的精子计数在发育过程中稳定地增加,并在四月龄时达到峰值,直到此时,野生型小鼠和RIP3敲除小鼠之间的精子计数几乎没有差异。然后野生型小鼠的精子计数开始下降,而RIP3敲除小鼠的精子计数保持稳定,直到12月龄。即使在24月龄时,RIP3敲除小鼠的精子计数仍与4月龄野生型小鼠的精子计数相当。
RIP3的敲除防止与年龄相关的生殖能力下降
为了测试来自衰老的RIP3敲除小鼠的精子是否仍然起作用,我们建立了繁殖实验,将4月龄、13月龄和18月龄雄性小鼠与几对10周龄野生型雌性小鼠配对。野生型和RIP3敲除4月龄雄性小鼠均完全可育,并且两组产下的幼崽数量均相似。然而,对于13月龄小鼠,在20只野生型雄性小鼠中,只有9只产下幼崽,而在23只RIP3敲除雄性中,有18只仍可育。这种差异在18月龄雄性小鼠中更为明显。在该月龄的22只野生型雄性小鼠中,只有4只仍可育,而在22只RIP3敲除雄性小鼠中,有15只仍可育。我们随后通过将一对10周龄雌性小鼠与每只雄性在笼子中配对,并每隔一个月换一对新的雌性,来测量野生型小鼠和RIP3敲除雄性小鼠的生殖寿命(Hofmann等,2015)。监测每只雄性最后一次产仔的月龄,结果表明,野生型小鼠平均在16月龄左右丧失产仔能力,而RIP3敲除小鼠直到22月龄才丧失这种能力。
RIP3在睾丸中的精原细胞、精母细胞和塞尔托利氏细胞中的表达
为了研究造成延迟的生殖系统衰老表型的潜在机制,我们首先使用免疫组织化学方法(IHC)检查了RIP3表达。我们注意到野生型曲精小管内的细胞被抗RIP3抗体阳性染色。相反,在RIP3敲除小鼠的曲精小管中未观察到染色,证实了抗体的特异性。
通过用抗RIP3抗体和其他先前描述的细胞类型特异性标志物对来自性成熟野生型小鼠(8周龄)的睾丸切片进行免疫共染色,进一步分析了来自睾丸的特定细胞类型。RIP3表达在表达UTF1的生殖系精原细胞中(Jung等人,2014;van Bragt等人,2008)和在表达GATA-1的塞尔托利氏细胞中很明显(Tsai等人,2006)。然而,位于曲精小管外部的产生睾酮的莱氏细胞(由HSD3B1标记(Chang等人,2011))不表达RIP3。在解剖睾丸并将细胞铺在载玻片上并再次通过免疫共染色分析后,进一步证实了这些细胞类型中每一种的RIP3表达。细胞形状因采用该方法铺展而改变,但单个细胞更加清晰可见。与IHC染色结果一致,精原细胞和塞尔托利氏细胞对RIP3染色呈阳性,而莱氏细胞则不是。此外,当用特异性标志物SMAD3染色时,未被IHC标记的曲精小管内的原代精子细胞则清晰可见(Hentrich等人,2011),并且这些细胞表达RIP3。曲精小管内的细胞,即睾丸的精子产生单位,都对RIP3表达呈阳性,这一事实提出了这些细胞与年龄相关的消耗贯穿于坏死性凋亡的可能性。
RIP3底物MLKL在衰老的野生型小鼠的曲精小管中被磷酸化
回想起RIP3通过使假激酶MLKL的丝氨酸345磷酸化来转导坏死性凋亡信号,我们使用抗MLKL的磷酸丝氨酸345的抗体来分析幼龄和老龄小鼠的睾丸。在18月龄野生型小鼠睾丸中的中心管腔周围的曲精小管细胞中检测到磷酸化的MLKL(磷酸MLKL),而在8周龄野生型小鼠的相同组织区域中未检测到磷酸MLKL,在18月龄RIP3敲除小鼠中也未检测到。对各个月龄和基因型组的磷酸MLKL染色的定量分析表明,在老龄野生型小鼠的曲精小管中大量存在坏死性凋亡激活标志物,即丝氨酸345磷酸化,而在幼龄和RIP3敲除小鼠中则不存在,因此表明这些在曲精小管中表达RIP3的细胞的坏死性凋亡可能触发雄性性器官的衰老。一致地是,在18和24月龄野生型小鼠的睾丸提取物中,通过蛋白质免疫印迹检测到磷酸MLKL,而在同龄RIP3敲除小鼠的提取物中则未检测到。
为了进一步确定衰老的曲精小管中显示坏死性凋亡阳性标志物的确切细胞类型,我们使用荧光结合的抗磷酸MLKL抗体对睾丸切片进行免疫组织化学染色,并与特异性标记曲精小管中不同细胞类型的抗体共染色。将特异性表达UTF1的精原细胞与抗磷酸MLKL抗体共染色。另一方面,塞尔托利氏细胞即使表达RIP3,也未显示出磷酸MLKL染色。不足为奇的是,不具有RIP3表达的莱氏细胞也不会被磷酸MLKL抗体染色。
在衰老过程中莱氏细胞中凋亡的激活
睾丸中产生性激素的莱氏细胞不表达RIP3,但是在老龄小鼠睾丸中,激素水平下降并且莱氏细胞也消失了。因此,我们使用IHC检查了野生型小鼠和RIP3敲除小鼠的衰老睾丸中胱天蛋白酶原-3(已知的凋亡的标志物)和胱天蛋白酶原-8的切割状态。在18和36月龄小鼠的野生型莱氏细胞中检测到切割的胱天蛋白酶原-3和切割的胱天蛋白酶原-8,而在同龄RIP3敲除小鼠中未观察到此类信号。使用衰老的野生型睾丸提取物通过蛋白质免疫印迹也检测到切割的胱天蛋白酶-3,但在RIP3敲除睾丸中未检测到。因此,莱氏细胞很可能经历凋亡,这是衰老过程中对曲精小管的坏死性凋亡的继发性反应。
空的曲精小管中的胱天蛋白酶8水平在衰老过程中降低
我们还使用免疫组织化学方法检查了高龄野生型小鼠睾丸中相对于RIP3的胱天蛋白酶8水平。在衰老的野生型小鼠中,曲精小管中的胱天蛋白酶8水平降低,显示出细胞消耗的迹象,而在莱氏细胞中则升高。该胱天蛋白酶8的降低可能解释了在衰老小鼠的曲精小管中如何发生坏死性凋亡而不是凋亡。
MLKL的敲除也延迟了小鼠生殖器官的衰老
RIP3敲除小鼠的延迟的睾丸衰老表型和衰老的野生型小鼠精原细胞中坏死性凋亡激活标志物的检测表明,坏死性凋亡可能是睾丸衰老的潜在原因。为了进一步研究可能性,我们还鉴定了MLKL敲除小鼠的与衰老相关的表型。我们首先称重15月龄野生型、RIP3敲除和MLKL敲除(MLKL-/-)小鼠。MLKL敲除小鼠和RIP3敲除小鼠的重量之间没有显著差异,并且这两种敲除基因型的小鼠在该月龄时的体重都低于野生型小鼠。我们还分析了衰老的MLKL敲除小鼠(15月龄)的精囊和曲精小管。与野生型小鼠中发生的明显的衰老相比,MLKL敲除小鼠的精囊保持年轻的外观,表现出与RIP3敲除小鼠相同的表型。此外,虽然大多数来自15月龄野生型小鼠的精囊重量超过1,000毫克,但几乎所有来自同龄MLKL和RIP3敲除的精囊重量都低于1,000毫克。一致地是,MLKL敲除小鼠和RIP3敲除小鼠的睾酮水平也显著高于同龄野生型小鼠的睾酮水平。此外,与RIP3敲除小鼠的小管类似,非常少(<2%)的来自MLKL敲除小鼠的曲精小管在15月龄时是空的,而超过12%的来自同龄野生型小鼠的曲精小管已经空了。最后,16月龄MLKL和RIP3敲除小鼠的生育率也显著高于同龄野生型小鼠的生育率。
睾丸中坏死性凋亡的诱导消耗曲精小管中的细胞
为了直接证明睾丸中的坏死性凋亡足以引起雄性生殖系统衰老,我们向2月龄小鼠的睾丸注射了TNF-α、Smac模拟物和已知的坏死性凋亡刺激物胱天蛋白酶抑制剂z-VAD-FMK(以下简称“TSZ”)的组合(He等人,2009)。将TSZ直接注射到睾丸中会诱导MLKL磷酸化。注射了TSZ的野生型睾丸的曲精小管内明显存在磷酸-MLKL,但经TSZ处理的RIP3敲除或MLKL敲除睾丸中不存在,证实了在TSZ注射后睾丸中坏死性凋亡的激活。此外,当从野生型睾丸中分离细胞,然后用TSZ处理,之后用抗磷酸-MLKL抗体和细胞类型特异性标志物染色时,曲精小管中的细胞(包括精原细胞、塞尔托利氏细胞和精母细胞)的磷酸-MLKL染色为阳性,而曲精小管外的莱氏细胞为阴性。单次TSZ注射72小时后,在睾丸中诱导坏死性凋亡的后果变得显而易见。至此,大约25%的野生型曲精小管是空的,而来自RIP3和MLKL敲除小鼠的曲精小管几乎没有受到影响。
睾丸坏死性凋亡的诱导加速了雄性生殖系统的衰老
除了在TSZ注射3月龄小鼠后监测这些短期作用外,我们在注射后还等了三个月,并评估了小鼠睾丸中诱导的坏死性凋亡的长期作用。有趣的是,TSZ注射后三个月,野生型受体小鼠的精囊与来自15月龄以上的小鼠的精囊一样大。然而,在其睾丸的相同的TSZ处理后,在RIP3敲除小鼠和MLKL敲除小鼠中未观察到精囊的这种增大。此外,在注射后三个月,超过30%的野生型曲精小管仍为空的,而RIP3敲除小鼠和MLKL敲除小鼠的那些则看起来完全正常,没有任何可观察到的细胞损失。
我们还测试了在TSZ处理后3个月TSZ处理的小鼠的生育率。向野生型小鼠的睾丸中对照注射生理盐水不会影响生育率,并且小鼠仍保持100%可育,但TSZ注射使生育率降低了87.5%(8只中只有1只可育)。相比之下,TSZ注射后,8只RIP3敲除小鼠中的6只和8只MLKL敲除小鼠中的7只仍可育。
RIP1激酶抑制剂阻断雄性生殖系统的衰老
坏死性凋亡在小鼠雄性生殖系统衰老中的作用的确定表明了针对衰老过程的药物干预的可行性。因此,我们通过以150mg/kg和300mg/kg的剂量掺入小鼠食物中,评价了来自我们实验室的一种新确定的、高效且高度特异性的RIP1激酶抑制剂的作用(下文称为“RIPA-56”)(Ren等人,2017)。在给小鼠饲喂浓度较高的含RIPA-56的食物一周后,我们首先通过将TSZ注射到2月龄小鼠的睾丸中来测试RIPA-56对睾丸中坏死性凋亡的作用。RIPA-56以剂量依赖的方式阻断了TSZ诱导的磷酸-MLKL在睾丸中的出现,并能够以300mg/kg的剂量完全阻断坏死性凋亡。
我们随后选择300mg/kg的剂量连续饲喂13月龄雄性野生型小鼠两个月,以研究阻断坏死性凋亡对睾丸的长期影响。两个月后,饲喂RIPA-56的小鼠体重比饲喂对照食物的小鼠轻。经RIPA-56处理的小鼠的精囊保持质量(大部分约为1000毫克),而对照小鼠的精囊在同一时期显著生长,其中大多数重量超过2,000毫克。此外,RIPA-56处理的小鼠的睾酮水平仍然很高,而对照小鼠的睾酮水平却下降。一致地是,对照小鼠中超过12%的曲精小管是空的,而在RIPA-56处理的小鼠中几乎没有任何曲精小管是空的。最后,RIPA-56处理的小鼠的生育率大大高于对照小鼠,其中RIPA-56饮食的25只小鼠中有19只可育,而正常饮食的23只小鼠中只有6只产下后代。总体而言,饲喂的小鼠表现出更年轻的总体雄性衰老指标,包括体重、脂肪沉积、性欲(通过对同笼雌性小鼠的性反应证明)、生育力、肌肉质量和前列腺增生。
代表性的RIP1、RIP3和MLKL激酶抑制剂阻断雄性生殖系统的衰老
与我们的基因敲除结果一致,示例性的坏死性凋亡的抑制剂,包括RIP1、RIP3和MLKL的抑制剂对雄性衰老具有相似的逆转作用,所述雄性衰老包括睾丸坏死性凋亡、睾酮水平、体重增加、肌肉质量下降和前列腺增生。
表1-3的化合物的实验方案是基于针对RIPA-56使用的那些。将每种抑制剂以100mg/kg和/或300mg/kg的剂量混合到小鼠食物中,并连续饲喂13月龄雄性小鼠两个月。用代表性抑制剂饲喂两个月后,饲喂的小鼠(现为15月龄)的精囊保持年轻的形态和质量(大多数约为1,000mg),而饲喂对照食物的小鼠精囊在同一时期显著生长,其中大多数大于2,000mg。一致地,饲喂抑制剂的小鼠的睾酮水平保持很高,而普通食物饮食的小鼠的睾酮水平下降。另外,当检查这些小鼠的曲精小管时,多于12%的来自对照小鼠的曲精小管是空的,而来自抑制剂饲喂的小鼠的睾丸很少有曲精小管是空的。总体而言,处理的小鼠表现出更年轻的总体雄性衰老指标,包括体重、脂肪沉积、性欲(通过对同笼雌性小鼠的性反应证明)、生育力、肌肉质量和前列腺增生。
表1.RIP1抑制剂
5-((1H-吲哚-3-基)甲基)-3-甲基-2-硫代咪唑烷-4-酮(Nec-1)
(S)-苯基(5-苯基-4,5-二氢-1H-吡唑-1-基)甲酮
5-((1H-吲哚-3-基)甲基)-3-甲基-2-硫代咪唑烷-4-酮(Nec-1s)
3-甲基-5-((7-甲基-1H-吲哚-3-基)甲基)咪唑烷-2,4-二酮
(R)-5-((7-氯-1H-吲哚-3-基)甲基)-3-甲基咪唑烷-2,4-二酮
(R)-5-((7-氯-1H-吲哚-3-基)甲基)-3-(4-(3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯基)丁基)咪唑烷-2,4-二酮(帕纳替尼-Nec1s)
(S)-2,2-二甲基-1-(5-苯基-4,5-二氢-1H-吡唑-1-基)丙-1-酮(GSK963)
(S)-2,2-二甲基-1-(5-苯基-4,5-二氢-1H-吡唑-1-基)丙-1-酮
(S)-1-(4-(5-苯基-4,5-二氢-1H-吡唑-1-羰基)哌啶-1-基)乙酮
(S)-2,2-二甲基-1-(5-(吡啶-2-基)-4,5-二氢-1H-吡唑-1-基)丙-1-酮
(S)-1-(4-(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-羰基)哌啶-1-基)乙酮
1-(4-(4-氨基呋喃并[2,3-d]嘧啶-5-基)苯基)-3-(2-氟-5-(三氟甲基)苯基)脲(Cpd27)
3-甲基-5-((7-甲基-1H-吲哚-3-基)甲基)咪唑烷-2,4-二酮
(R)-5-((7-氯-1H-吲哚-3-基)甲基)-3-甲基咪唑烷-2,4-二酮
3-苄基-6,7-二氢-3H-环戊烷并[4,5]噻吩并[2,3-d]嘧啶-4(5H)-酮
N-(3-氯-2,6-二氟苄基)-4-环丙基-1,2,3-噻二唑-5-甲酰胺
(S)-N-(1-(2-氯-6-氟苯基)乙基)-5-氰基-1-甲基-1H-吡咯-2-甲酰胺
(S)-N-(1-(2-氯-6-氟苯基)乙基)-4-环丙基-1,2,3-噻二唑-5-甲酰胺
N-苄基-N-羟基-2,2-二甲基丁酰胺
N-(4-氟苄基)-N-羟基-2,2-二甲基丁酰胺
N-(2,4-二氟苄基)-N-羟基-2,2-二甲基丁酰胺
N-(3,4-二氟苄基)-N-羟基-2,2-二甲基丁酰胺
N-羟基-2,2-二甲基-N-(2,3,4-三氟苄基)丁酰胺
N-羟基-2,2-二甲基-N-(3,4,5-三氟苄基)丁酰胺
N-羟基-2,2-二甲基-N-(2,3,5-三氟苄基)丁酰胺
(2-(3-氟苯基)吡咯烷-1-基)(1-(三氟甲基)环戊基)甲酮
(2-(3-氟苯基)吡咯烷-1-基)(1-(三氟甲基)环丁基)甲酮
(S)-1-(2,2-二甲基丁-3-烯酰基)-4-苯基氮杂环丁-2-酮
(S)-2,2-二甲基-1-(2-苯基氮杂环丁-1-基)丁-3-炔-1-酮
(S)-1-(2,2-二甲基丁酰基)-4-苯基氮杂环丁-2-酮,
或WO2016/101885或WO2016/101887公开的RIP1抑制剂。
表2.RIP3抑制剂
2-(4-(5-(甲基氨基甲酰基)-1H-苯并[d]咪唑-1-基)苯基)乙酸叔丁酯(GSK'840)
3-(苯并[d]噻唑-5-基)-7-(1,3-二甲基-1H-吡唑-5-基)噻吩并[3,2-c]吡啶-4-胺(GSK'843)
N-(6-(异丙基磺酰基)喹啉-4-基)苯并[d]噻唑-5-胺(GSK'872)
N-[3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-4-噻唑基]-2-氟苯基]-2,6-二氟-苯磺酰胺(达拉菲尼)
3-(2-咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基-N-[4-[(4-甲基-1-哌嗪基)甲基]-3-(三氟甲基)苯基]-苯甲酰胺(帕纳替尼)
5-[[4-[(2,3-二甲基-2H-吲唑-6-基)甲基氨基]-2-嘧啶基]氨基]-2-甲基-苯磺酰胺(帕唑帕尼)
表3.MLKL抑制剂
(2E)-N-[4-[[(3-甲氧基-2-吡嗪基)氨基]磺酰基]苯基]-3-(5-硝基-2-噻吩基)-2-丙烯酰胺(Necrosulfonamide)
1,3,7-三甲基-8-(甲基磺酰基)-1H-嘌呤-2,6(3H,7H)-二酮(TC13-4)
(2,5-二甲氧基苄基磺酰基)-1,3,7-三甲基-1H-嘌呤-2,6(3H,7H)-二酮(TC13-58)
7-乙基-1,3-二甲基-8-(甲基磺酰基)-1H-嘌呤-2,6(3H,7H)-二酮(TC13-74)
1,7-二甲基-8-(甲基磺酰基)-3-(丙-2-炔基)-1H-嘌呤-2,6(3H,7H)-二酮(TC13-106)
2-(1,7-二甲基-8-(甲基磺酰基)-2,6-二氧代-1H-嘌呤-3(2H,6H,7H)-基)乙腈(TC13-107)
3-(3-(3-氯苯基)丙-2-炔-1-基)-8-((环丙基甲基)磺酰基)-1,7-二甲基-3,7-二氢-1H-嘌呤-2,6-二酮(TC13-119)
8-((2,5-二甲氧基苄基)磺酰基)-1,7-二甲基-3-(3-(2-(甲基氨基)吡啶-4-基)丙-2-炔-1-基)-3,7-二氢-1H-嘌呤-2,6-二酮(TC13-127)
3-(3-(3-羟基苯基)丙-2-炔-1-基)-1,7-二甲基-8-(甲基磺酰基)-3,7-二氢-1H-嘌呤-2,6-二酮(TC13-172)
3-((4-(甲基(4-(3-(4-(三氟甲氧基)苯基)脲基)苯基)氨基)嘧啶-2-基)氨基)苯磺酰胺(化合物1)
另外的活性MLKL抑制剂在PCT/CN2018/077464中公开,包括表4和5的化合物。
表4.MLKL抑制剂
表5.MLKL抑制剂
睾丸中的坏死性凋亡是小鼠雄性生殖系统程序性衰老的途径
我们在8周龄、4月龄、18月龄和24月龄时对野生型小鼠和RIP3敲除小鼠的主要器官,包括小肠、脾、肺、肝、大肠、肾、心脏和大脑进行了组织学分析,并且未观察到在衰老过程中野生型和同龄RIP3敲除小鼠之间有明显差异。
在向幼龄野生型小鼠睾丸中给予一种坏死性凋亡刺激物之后,可以在其中模仿睾丸衰老的表型,包括精囊的扩大、空的曲精小管以及睾酮水平和生育率的降低,而在RIP3和MLKL敲除小鼠中则不能,这一发现表明坏死性凋亡引起雄性生殖系统衰老。一致地是,观察到MLKL上的磷酸丝氨酸345(一种坏死性凋亡激活标志物)仅存在于老龄野生型的曲精小管中(即在同龄RIP3或MLKL敲除小鼠的睾丸中不存在)进一步证实了这一结论。此外,缺少坏死性凋亡的核心成分(RIP3或MLKL)之一的小鼠的雄性生殖系统保持年轻的形态和功能,直到高龄。
然而,由老龄RIP3敲除小鼠所产下的后代比年轻雄性所产下的后代更不健康;RIP3敲除后代具有更高的产前和产后死亡率。我们对来自三只18月龄RIP3敲除小鼠和三只4月龄RIP3敲除小鼠的精子的基因组DNA进行了测序。18月龄敲除小鼠精子的平均突变负荷并不明显高于4月龄小鼠的平均突变负荷。因此,据基因组DNA测序可以确定,这些老龄RIP3敲除小鼠所产下的幼仔致死率的提高并非由于精子中突变的大量积累。后代不健康的更可能的原因可能是衰老的RIP3敲除小鼠的精子DNA中积累的氧化损伤,如DNA氧化损伤的生物标志物(36)8-羟基脱氧鸟苷(8-OHdG)的水平在18月龄RIP3敲除小鼠的精子中显著高于4月龄小鼠。此外,考虑到RIP3敲除小鼠的脑垂体激素LH和FSH随着年龄的增长而下降(就像野生型小鼠一样),显然,这些突变小鼠的配子和其他器官中也通常发生其他与年龄相关的DNA改变。这些结果表明,曲精小管中的坏死性凋亡是对年龄相关的、局部产生的细胞因子的TNF家族的生理反应。坏死性凋亡随后触发其余雄性生殖器官的衰老和其他与年龄相关的下游表型,例如睾酮减少和体重增加。其坏死性凋亡通过RIP3和MLKL的基因缺失阻断或通过RIPA-56药物阻断的小鼠确实显示与年龄相关的体重增加少得多。
睾丸中产生性激素的莱氏细胞不表达RIP3,在衰老的小鼠睾丸中,激素水平下降并且莱氏细胞也消失了。因此,我们使用IHC检查了在野生型小鼠和RIP3敲除小鼠的衰老睾丸中胱天蛋白酶原-3(凋亡的已知标志物)的切割状态。在18、24和36月龄小鼠的野生型莱氏细胞中检测到切割的胱天蛋白酶原-3,而在RIP3敲除小鼠中未观察到此类信号。使用衰老的野生型睾丸提取物通过蛋白质免疫印迹也检测到切割的胱天蛋白酶-3,但在RIP3敲除睾丸中不存在。这些结果表明,莱氏细胞在衰老过程中经历凋亡,这显然是坏死性凋亡的结果。
当小鼠从生殖系统衰老表型发作开始(13月龄)就开始饲喂含RIP1、RIP3或MLKL抑制剂的食物时,雄性生殖系统的衰老受到抑制。这一发现不仅进一步证实了坏死性凋亡是雄性生殖系统衰老的根本机制,而且还提供了延缓衰老的有效治疗方法。
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Claims (12)
1.一种治疗雄性衰老的方法,包括向有其需要的雄性给予坏死性凋亡抑制剂。
2.权利要求1所述的方法,其中所述坏死性凋亡抑制剂是RIP1、RIP3或MLKL抑制剂。
3.权利要求1所述的方法,其中所述坏死性凋亡抑制剂是选自以下的RIP1抑制剂:
5-((1H-吲哚-3-基)甲基)-3-甲基-2-硫代咪唑烷-4-酮(Nec-1);
(S)-苯基(5-苯基-4,5-二氢-1H-吡唑-1-基)甲酮;
5-((1H-吲哚-3-基)甲基)-3-甲基-2-硫代咪唑烷-4-酮(Nec-1s);
3-甲基-5-((7-甲基-1H-吲哚-3-基)甲基)咪唑烷-2,4-二酮;
(R)-5-((7-氯-1H-吲哚-3-基)甲基)-3-甲基咪唑烷-2,4-二酮;
(R)-5-((7-氯-1H-吲哚-3-基)甲基)-3-(4-(3-(咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基苯基)丁基)咪唑烷-2,4-二酮(帕纳替尼-Nec 1s);
(S)-2,2-二甲基-1-(5-苯基-4,5-二氢-1H-吡唑-1-基)丙-1-酮(GSK963);
(S)-2,2-二甲基-1-(5-苯基-4,5-二氢-1H-吡唑-1-基)丙-1-酮;
(S)-1-(4-(5-苯基-4,5-二氢-1H-吡唑-1-羰基)哌啶-1-基)乙酮;
(S)-2,2-二甲基-1-(5-(吡啶-2-基)-4,5-二氢-1H-吡唑-1-基)丙-1-酮;
(S)-1-(4-(5-(3,5-二氟苯基)-4,5-二氢-1H-吡唑-1-羰基)哌啶-1-基)乙酮;
1-(4-(4-氨基呋喃并[2,3-d]嘧啶-5-基)苯基)-3-(2-氟-5-(三氟甲基)苯基)脲(Cpd27);
3-甲基-5-((7-甲基-1H-吲哚-3-基)甲基)咪唑烷-2,4-二酮;
(R)-5-((7-氯-1H-吲哚-3-基)甲基)-3-甲基咪唑烷-2,4-二酮;
3-苄基-6,7-二氢-3H-环戊烷并[4,5]噻吩并[2,3-d]嘧啶-4(5H)-酮;
N-(3-氯-2,6-二氟苄基)-4-环丙基-1,2,3-噻二唑-5-甲酰胺;
(S)-N-(1-(2-氯-6-氟苯基)乙基)-5-氰基-1-甲基-1H-吡咯-2-甲酰胺;
(S)-N-(1-(2-氯-6-氟苯基)乙基)-4-环丙基-1,2,3-噻二唑-5-甲酰胺;
N-苄基-N-羟基-2,2-二甲基丁酰胺;
N-(4-氟苄基)-N-羟基-2,2-二甲基丁酰胺;
N-(2,4-二氟苄基)-N-羟基-2,2-二甲基丁酰胺;
N-(3,4-二氟苄基)-N-羟基-2,2-二甲基丁酰胺;
N-羟基-2,2-二甲基-N-(2,3,4-三氟苄基)丁酰胺;
N-羟基-2,2-二甲基-N-(3,4,5-三氟苄基)丁酰胺;
N-羟基-2,2-二甲基-N-(2,3,5-三氟苄基)丁酰胺;
(2-(3-氟苯基)吡咯烷-1-基)(1-(三氟甲基)环戊基)甲酮;
(2-(3-氟苯基)吡咯烷-1-基)(1-(三氟甲基)环丁基)甲酮;
(S)-1-(2,2-二甲基丁-3-烯酰基)-4-苯基氮杂环丁-2-酮;
(S)-2,2-二甲基-1-(2-苯基氮杂环丁-1-基)丁-3-炔-1-酮;和
(S)-1-(2,2-二甲基丁酰基)-4-苯基氮杂环丁-2-酮。
4.权利要求1所述的方法,其中所述坏死性凋亡抑制剂是选自以下的RIP3抑制剂:
2-(4-(5-(甲基氨基甲酰基)-1H-苯并[d]咪唑-1-基)苯基)乙酸叔丁酯(GSK'840);
3-(苯并[d]噻唑-5-基)-7-(1,3-二甲基-1H-吡唑-5-基)噻吩并[3,2-c]吡啶-4-胺(GSK'843);
N-(6-(异丙基磺酰基)喹啉-4-基)苯并[d]噻唑-5-胺(GSK'872);
N-[3-[5-(2-氨基-4-嘧啶基)-2-(1,1-二甲基乙基)-4-噻唑基]-2-氟苯基]-2,6-二氟-苯磺酰胺(达拉菲尼);
3-(2-咪唑并[1,2-b]哒嗪-3-基乙炔基)-4-甲基-N-[4-[(4-甲基-1-哌嗪基)甲基]-3-(三氟甲基)苯基]-苯甲酰胺(帕纳替尼);和
5-[[4-[(2,3-二甲基-2H-吲唑-6-基)甲基氨基]-2-嘧啶基]氨基]-2-甲基-苯磺酰胺(帕唑帕尼)。
5.权利要求1所述的方法,其中所述坏死性凋亡抑制剂是选自以下的MLKL抑制剂:
(2E)-N-[4-[[(3-甲氧基-2-吡嗪基)氨基]磺酰基]苯基]-3-(5-硝基-2-噻吩基)-2-丙烯酰胺(Necrosulfonamide);
1,3,7-三甲基-8-(甲基磺酰基)-1H-嘌呤-2,6(3H,7H)-二酮(TC13-4);
8-(2,5-二甲氧基苄基磺酰基)-1,3,7-三甲基-1H-嘌呤-2,6(3H,7H)-二酮(TC13-58);
7-乙基-1,3-二甲基-8-(甲基磺酰基)-1H-嘌呤-2,6(3H,7H)-二酮(TC13-74);
1,7-二甲基-8-(甲基磺酰基)-3-(丙-2-炔基)-1H-嘌呤-2,6(3H,7H)-二酮(TC13-106);
2-(1,7-二甲基-8-(甲基磺酰基)-2,6-二氧代-1H-嘌呤-3(2H,6H,7H)-基)乙腈(TC13-107);
3-(3-(3-氯苯基)丙-2-炔-1-基)-8-((环丙基甲基)磺酰基)-1,7-二甲基-3,7-二氢-1H-嘌呤-2,6-二酮(TC13-119);
8-((2,5-二甲氧基苄基)磺酰基)-1,7-二甲基-3-(3-(2-(甲基氨基)吡啶-4-基)丙-2-炔-1-基)-3,7-二氢-1H-嘌呤-2,6-二酮(TC13-127);
3-(3-(3-羟基苯基)丙-2-炔-1-基)-1,7-二甲基-8-(甲基磺酰基)-3,7-二氢-1H-嘌呤-2,6-二酮(TC13-172);和
3-((4-(甲基(4-(3-(4-(三氟甲氧基)苯基)脲基)苯基)氨基)嘧啶-2-基)氨基)苯磺酰胺(化合物1)。
6.权利要求1所述的方法,其中所述雄性衰老选自与年龄相关的低睾酮、低性欲、勃起功能障碍、体重增加、肌肉质量或肌张力降低和前列腺增生。
7.权利要求1所述的方法,其中所述方法还包括向雄性给予用于治疗雄性衰老的第二种不同的药物。
8.权利要求1所述的方法,其中所述方法还包括诊断雄性衰老的先前步骤,或检测得到的雄性衰老的减轻或逆转的后续步骤。
9.一种药物组合物,其包含坏死性凋亡抑制剂和用于治疗雄性衰老的第二种不同的药物。
10.权利要求9所述的药物组合物,其中所述不同的药物选自雄激素,包括外源性和内源性同化雄性类固醇、内源性雄激素刺激剂(例如,顺式克罗米酚、克罗米酚)、雌激素抑制剂(例如,抗雌激素剂,如克罗米酚、反式克罗米酚、他莫昔芬、雷洛昔芬)、生长激素(例如,HGH)。
11.权利要求9所述的药物组合物,其中所述不同的药物选自:睾酮、普拉睾酮(去氢表雄酮、DHEA)、雄烯二酮(A4)、雄烯二醇(A5)、二氢睾酮(DHT)、1-雄烯二醇、1-雄烯二酮、勃雄二醇、勃拉睾酮、勃地酮、勃二酮、卡普睾酮、氯睾酮、达那唑、脱氢氯甲基睾酮、去氧甲基睾酮、屈他雄酮、乙雌烯醇、氟甲睾酮、甲酰勃龙、夫拉扎勃、孕三烯酮、4-羟基睾酮、美雄诺龙、美睾酮、美替诺龙、去氢甲睾酮、美雄醇、甲基屈他雄酮、甲二烯诺龙、甲基-1-睾酮、甲基去甲睾酮、甲基睾酮、美曲勃龙、米勃龙、诺龙、19-去甲雄烯二酮、诺勃酮、诺司替勃、诺乙雄龙、羟勃龙、氧雄龙、羟甲睾酮、羟甲烯龙、普罗斯它诺唑、奎勃龙、司坦唑醇、司腾勃龙、1-睾酮、四氢孕三烯酮和群勃龙。
12.权利要求9所述的组合物,其中所述组合物为单位剂型。
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CN114981298A (zh) | 2019-12-12 | 2022-08-30 | 听治疗有限责任公司 | 用于预防和治疗听力损失的组合物和方法 |
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