CN108601753A - 抑制胆碱向三甲胺(tma)的转化的方法 - Google Patents
抑制胆碱向三甲胺(tma)的转化的方法 Download PDFInfo
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- CN108601753A CN108601753A CN201680070716.6A CN201680070716A CN108601753A CN 108601753 A CN108601753 A CN 108601753A CN 201680070716 A CN201680070716 A CN 201680070716A CN 108601753 A CN108601753 A CN 108601753A
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- choline
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Classifications
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- A61K31/166—Amides, e.g. hydroxamic acids having aromatic rings, e.g. colchicine, atenolol, progabide having the carbon of a carboxamide group directly attached to the aromatic ring, e.g. procainamide, procarbazine, metoclopramide, labetalol
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- C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
- C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
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- C07D213/04—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
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Abstract
本发明提供抑制个体中胆碱向三甲胺(TMA)的转化并降低TMAO的一种或多种方法,其包括向所述个体施用包含如式(I)中所示的化合物的一种或多种组合物:
Description
技术领域
本发明一般涉及抑制三甲胺产生的材料和方法。
背景技术
三甲胺(TMA)及其衍生物三甲胺-N-氧化物(TMAO)是与诸如肾病、糖尿病、三甲基胺尿症和心血管疾病(CVD)的病症有关的代谢物。CVD是一个通用术语,其涵盖影响心脏和血管的一系列病况,包括动脉粥样硬化、冠心病、脑血管疾病、心力衰竭、心肌病、动脉粥样硬化血栓性疾病、主动脉-髂骨疾病和外周血管疾病。CVD通常与涉及狭窄、堵塞、动脉瘤或一个或多个血管解剖或血栓形成(血块形成)的病况相关。与CVD相关的并发症包括但不限于心肌梗塞、中风、心绞痛、急性冠脉综合征、短暂性脑缺血发作、充血性心力衰竭、主动脉瘤、心房颤动或扑动、室性心律失常、心脏传导异常、需要血运重建和死亡。血运重建可以包括但不限于血管成形术、支架置入术、冠状动脉旁路移植术、维修或置换血管分流器或通路如动静脉瘘。与动脉粥样硬化血栓性疾病相关的并发症包括但不限于心肌梗塞、中风、肺栓塞、深静脉血栓形成。根据世界卫生组织,CVD是全球死亡的主要原因,其中超过75%的死亡在低收入和中等收入国家发生。世界卫生组织简报第317号,2015年1月更新。世界卫生组织预测,到2030年,糖尿病将成为第七大死因。世界卫生组织简报第312号,2015年1月更新。包括CVD和糖尿病的与TMA和TMAO相关的病况的预防和管理是一个重大的公共卫生问题。
发明内容
本公开至少部分地基于以下发现:式(I)、式(II)和式(III)的化合物通过肠道微生物群抑制胆碱代谢,引起三甲胺(TMA)和三甲胺N-氧化物(TMAO)的形成降低。本公开提供用于例如在体外和体内抑制胆碱向TMA的转化以改善或维持心血管、脑血管和外周血管健康并改善或预防与TMA和TMAO相关的病况的组合物和方法。
一方面,本发明提供通过细菌抑制胆碱向三甲胺(TMA)的转化的一种或多种方法,该方法包括使所述细菌与如式(I)中所示的一种或多种化合物接触:
其中R1选自氰酸酯、异氰酸酯、硫氰酸酯、异硫氰酸酯、腈、异腈或巯基;n’选自0、1、2、3、4、5、6、7、8、9或10;且R2选自烷基、支链烷基、杂烷基、环烷基、杂环烷基、芳基或取代的羰基;其中,当R2为苯基时,R2被独立地选自烷基、支链烷基、杂烷基、环烷基、杂环烷基、卤基或芳基的0、1或2个基团取代;条件是当R2为杂烷基或杂环烷基时,这一个或多个杂原子不是S;并且条件是当n'为2时,R2不是未取代的苯基。
另一方面,本发明提供通过细菌来抑制胆碱向三甲胺(TMA)的转化的一种或多种方法,该方法包括使所述细菌与如式(II)中所示的如式(I)中所示的一种或多种化合物接触,
其中n’和R2如对于式(I)所定义。
另一方面,本发明提供通过细菌来抑制胆碱向三甲胺(TMA)的转化的一种或多种方法,该方法包括使所述细菌与如式(III)中所示的如式(I)中所示的一种或多种化合物接触:
其中R3选自氢、烷基或芳基;且R4为芳基;其中,当R4为苯基时,R4被独立地选自烷基、支链烷基、杂烷基、环烷基、杂环烷基、卤基或芳基的0、1或2个基团取代;条件是当R4被杂烷基或杂环烷基取代时,一个或多个杂原子不是S。
一方面,本发明提供抑制个体中胆碱向三甲胺(TMA)的转化的一种或多种方法。所述方法包括向所述个体施用如式(I)中所示的一种或多种化合物:
其中R1选自氰酸酯、异氰酸酯、硫氰酸酯、异硫氰酸酯、腈、异腈或巯基;n’选自0、1、2、3、4、5、6、7、8、9或10;且R2选自烷基、支链烷基、杂烷基、环烷基、杂环烷基、芳基或取代的羰基;其中,当R2为苯基时,R2被独立地选自烷基、支链烷基、杂烷基、环烷基、杂环烷基、卤基或芳基的0、1或2个基团取代;条件是当R2为杂烷基或杂环烷基时,一个或多个杂原子不是S;并且条件是当n'为2时,R2不是未取代的苯基。所述化合物以有效抑制个体中由胆碱形成三甲胺(TMA)的量施用。
一方面,本发明提供改善与个体中胆碱向三甲胺(TMA)的转化相关的病况的一种或多种方法,该方法包括向所述个体施用如式(I)中所示的一种或多种化合物:
其中R1选自氰酸酯、异氰酸酯、硫氰酸酯、异硫氰酸酯、腈、异腈或巯基;n’选自0、1、2、3、4、5、6、7、8、9或10;且R2选自烷基、支链烷基、杂烷基、环烷基、杂环烷基、芳基或取代的羰基;其中,当R2为苯基时,R2被独立地选自烷基、支链烷基、杂烷基、环烷基、杂环烷基、卤基或芳基的0、1或2个基团取代;条件是当R2为杂烷基或杂环烷基时,一个或多个杂原子不是S;并且条件是当n'为2时,R2不是未取代的苯基。所述化合物以有效治疗或预防个体中与胆碱有关的三甲胺(TMA)相关的疾病或病况的量施用。
本发明还提供改善或维持心血管健康的一种或多种方法。一种方法包括向个体施用包含以改善或维持心血管健康的量的如本文所述的如式(I)、式(II)或式(III)中所示的化合物的一种或多种组合物。本发明还提供改善个体中与胆碱向三甲胺(TMA)的转化相关的病况的一种或多种方法。一种方法包括向所述个体施用一种或多种组合物,该组合物包含以有效改善所述病况的量的如本文所述的如式(I)、式(II)或式(III)中所示的化合物。在一些实施方案中,所述病况是三甲基胺尿症、肾病、糖尿病或心血管疾病,例如心绞痛、心律不齐、动脉粥样硬化、心肌病、充血性心力衰竭、冠状动脉疾病(CAD)、颈动脉疾病、心内膜炎、冠状动脉血栓形成、心肌梗塞(MI)、高血压/高血压症、高胆固醇血症/高脂血症、外周动脉疾病(PAD)或中风。
本发明还提供式(I)、式(II)或式(III)的化合物在体内或体外抑制胆碱向TMA的转化,以改善或维持心血管健康以及改善与胆碱向TMA的转化相关的病况的用途。还提供式(I)、式(II)或式(III)的化合物,其用于在体内或体外抑制胆碱向TMA的转化,以改善或维持心血管健康以及改善与胆碱向TMA的转化相关的病况。
上述总结并非旨在限定本发明的每个方面,而且在其它部分描述了其它的方面,诸如具体实施方式。此外,本发明包括(作为附加方面)以任何方式在范围上比由上文示出的特定段落所定义的变体更为狭义的本发明的全部实施方案。例如,本发明的某些方面被描述为属,并且应当了解属的各个成员各自是本发明的一个方面。另外,应当将以属来描述或者选择属的成员的方面理解为涵盖所述属的两个或更多个成员的组合。对于以“一个”或“一种”来描述或进行权利要求的本发明的方面,应当了解这些术语意味着“一个(种)或多个(种)”,除非上下文明确要求更受限制的含义。术语“或者”应该理解为涵盖了另选的或共同的条目,除非上下文明确另有要求。如果本发明的方面被描述成“包含”特征,则实施方案还考虑了“由…所述特征组成”或者“基本上由…所述特征组成”。
具体实施方式
由驻留在哺乳动物肠道中的细菌合成的三甲胺(TMA)在肝脏中被氧化为三甲胺氧化物(TMAO)。TMA的示例性前体包括胆碱、甜菜碱、磷脂酰胆碱、甘油磷酸胆碱、TMAO、鞘磷脂和卵磷脂,其中的许多来自饮食来源,例如全蛋和牛肝。不希望受特定机制或生物化学途径所束缚,通过甘氨酰基酶:胆碱三甲胺裂解酶(CutC)促进胆碱向TMA的厌氧转化。Craciun等人,Proc.Natl.Acad.Sci.(2012),109:21307-21312。个体肠道中由细菌引起胆碱向TMA的转化降低引起从肠吸收的TMA降低,引起肝脏中由黄素单加氧酶3(FMO3)酶使TMA氧化成TMAO后血浆TMAO的随后降低。Wang等人,Nature(2011),472:57-63。较低的血浆TMAO水平与人类主要心血管事件的较低发生率有关。Tang等人,NEJM(2013)368:1575-1584。胆碱向TMA的转化可以由一种细菌介导或者包含涉及两种、三种或更多种细菌的多步骤过程。
除非另外指明,否则本文提及的所有测量均在约22℃至25℃(即室温)下进行。
如本文所用,术语“个体”包括人类和其它类型的共享TMAO途径的哺乳动物,诸如家畜,包括但不限于家犬(犬科动物)、猫(猫科动物)、马、牛、雪貂、兔、猪、大鼠、小鼠、沙鼠、仓鼠、马等。
各种各样的个体可能希望降低细菌在其消化道中产生的TMA水平。例如,被诊断患有心血管疾病的个体可以由医师指导以采用处方药或者改变生活方式,从而调制血液胆固醇水平以降低严重心血管事件的风险。其它未曾诊断为心血管疾病但希望改善或维持心血管健康的个体也可能希望通过降低由消化道细菌产生的TMA水平来降低血浆TMAO水平。如本文进一步描述,TMA降低(以及引申开来,TMAO)通过本文所述的组合物实现,其包括例如包含异硫氰酸酯如式(I)、式(II)或式(III)的化合物的饮食补充剂。
如本文所用,“剂量”是指根据可靠的医学经验,包含一定量适于在单个场合给药的药物活性成分的药物(如液体药物或口服剂量单元)的体积。剂型可口服。在一个示例中,所述剂型可为液体药物,并且可为约30mL,在另一个示例中为约25mL,在另一个示例中为约20mL,在另一个示例中为约15mL,并且在另一个示例中为约10mL。在另一个示例中,液体药物的剂量可为约10mL至约75mL,在另一个示例中约15mL至约50mL,在另一个示例中约25mL至约40mL,并且在另一个示例中约28mL至约35mL。在另一个示例中,所述剂型可为固体剂型,并且可为约5g至约25mg,在另一个示例中约3g至约100mg,在另一个示例中约2g至约250mg,在另一个示例中约1.6g至约500mg,并且在另一个示例中约1g至约750mg。在一个示例中,所述剂型可为固体剂型,其中一个剂量为约3g,并且在另一个示例中一个剂量为约1.6g。给定液体剂量大小下,可调节活性成分的浓度以提供适当的活性物质剂量。在一个示例中,所述剂量旨在每4小时,在另一个示例中每6小时,在另一个示例中每8小时,并且在另一个示例中每12小时服用。
如本文所用,“药物”是指如药剂的药物,包括处方药物、非处方药物、柜台后药物、以及它们的组合。在一些示例中,药物可为补充剂,其可包含维生素、矿物质和植物药材(VMS)。
药物组合物可为任何适宜形式,包括液体组合物和固体口服剂型。液体组合物的非限制性示例可包括糖浆(包括咳嗽糖浆)、呼吸系统用制剂(包括MSR感冒/流感药物)、饮料、补给水、泡沫组合物、凝胶组合物、悬浮于液体制剂中的颗粒、凝胶或泡沫中的固体、生理盐水洗剂、以及它们的组合。固体口服剂型的非限制性示例可以包括片剂、胶囊剂、囊片、小药囊、舌下剂型、颊面剂型、软凝胶(包括LiquiCapsTM和其它液体填充的胶囊剂)、可溶性剂型(包括可溶性条)、膜、口香糖(包括中心填充的口香糖)、软糖(包括中心填充的软糖)、锭剂、可食用食物(诸如食物条)、中心填充的片剂、粉剂、颗粒剂、粒料、微球体、纳米球体、小珠或彩色糖豆、以及它们的组合。片剂可包括压缩片剂、咀嚼片、可溶性片剂等。片剂可包括压缩片剂、咀嚼片、可溶性片剂等。在其它示例中,可将所述药物以膏剂形式施用于皮肤如在其它示例中,所述药物可被吸入如鼻喷剂或吸入剂。在其它示例中,所述药物可存在于饮料中如温热饮料。在其它示例中,所述药物可包含药物活性物质。在其它示例中,所述药物不包含药物活性物质和/或VMS,但是可通过凉爽感,至少部分缓解症状和/或提供健康有益效果。
所述药物可为可直接递送至口腔、喉咙和/或皮肤的形式。在一些示例中,所述药物组合物可经由递送装置递送,所述递送装置选自点滴器、泵、喷涂器、滴液器、经由鼻腔通道递送的生理盐水冲洗器、杯、瓶、罐、加压喷雾器、雾化器、吸气装置、可挤压小袋、电动注射器、泡罩卡、和其它包装和设备、以及它们的组合。喷涂器、雾化器和吸气装置可连有电池或电源。
本公开提供例如抑制胆碱向三甲胺(TMA)的转化的一种或多种方法、改善心血管健康的一种或多种方法、以及改善与胆碱向三甲胺(TMA)的转化相关的病况的一种或多种方法,其包括向个体施用包含式(I)、式(II)或式(III)的化合物的一种或多种组合物。下面描述组合物和方法的特征。章节标题是为了方便阅读,而并非旨在限制本身。全部本文件旨在作为统一的公开内容相关联,并且应当理解本文所述特征的全部组合均被考虑,即使特征的组合并非共同见于本文件的相同句子、段落或者章节之中。应该理解,本文所述的方法或化合物的任何特征可以全部或部分地删除,与本文所述的任何其它特征组合或替代本文所述的任何其它特征。
化合物
本公开的方法包括向个体施用包含式(I)中所示的化合物的一种或多种组合物:
其中R1选自氰酸酯、异氰酸酯、硫氰酸酯、异硫氰酸酯、腈、异腈或巯基;n’选自0、1、2、3、4、5、6、7、8、9或10;且R2选自烷基、支链烷基、杂烷基、环烷基、杂环烷基、芳基或取代的羰基;其中,当R2为苯基时,R2被独立地选自烷基、支链烷基、杂烷基、环烷基、杂环烷基、卤基或芳基的0、1或2个基团取代;条件是当R2为杂烷基或杂环烷基时,这一个或多个杂原子不是S;并且条件是当n'为2时,R2不是未取代的苯基。所述化合物以有效实现所需有益效果,例如抑制胆碱向TMA的转化,改善或维持心血管健康和/或改善与胆碱向TMA的转化相关的病况的量施用。
在一些情况下,R2选自甲基、乙基、丙基(诸如正丙基或异丙基)、丁基(诸如正丁基、异丁基、仲丁基或叔丁基)、戊基(例如,1-戊基、3-戊基、3-甲基丁基、2-甲基丁基)、己基(例如,1-己基)、庚基、辛基、壬基、癸基、环丙基、环丁基、环戊基、环己基、环庚基、环辛基、降冰片基、吗啉代基、哌啶代基、烷基氨基(例如,三烷基铵、3-(二乙基氨基)丙基、二甲基氨基、二乙基氨基、(叔丁氧基羰基)氨基、((叔丁氧基羰基)氨基)丁基)、苯基、取代的苯基、萘基、芳基羰基(例如,苯甲酰基)、烷基羰基、羧基、烷氧基羰基、氨基羰基、烷基氨基羰基、二苯甲基和α-甲基苄基。在一些情况下,R2为被1或2个选自下列的基团取代的苯基:甲基、乙基、丙基、丁基、烷氧基(例如,甲氧基、乙氧基)、烷硫基(例如,甲硫基、乙硫基)、氟、溴、氯、碘、(叔丁氧基羰基)氨基或
在各种实施方案中,R1为异硫氰酸酯。在一些情况下,所述化合物选自异硫氰酸仲丁酯和异硫氰酸乙酯。在本发明的各种方面中,当R1为异硫氰酸酯时,n'为0(即,不存在CH2)。在一些情况下,所述化合物选自异硫氰酸苄酯、异硫氰酸3-二乙基氨基丙酯、异硫氰酸3-(4-吗啉代)丙酯、异硫氰酸2-(4-吗啉代)乙酯和异硫氰酸2-哌啶代乙酯。
在各种实施方案中,当R1为异硫氰酸酯时,n'为至少1(例如,n'为至少1、至少2、至少3、至少4、至少5、至少6、至少7、至少8、至少9、或至少10)。
式(I)还包括由式(I)涵盖的任何化合物的一种或多种盐或溶剂化物。
在各种实施方案中,本公开的方法另外包括向个体施用包含如式(II)中所示的式(I)的化合物的一种或多种组合物:
其中n'和R2如对于式(I)所定义。所述化合物以有效抑制个体中胆碱向TMA的转化的量施用。在一些情况下,R2是卤芳基(例如,卤苯基)并且n’为2。
在各种方面,所述化合物是N-Boc-4-异硫氰酸根合丁胺或苯甲酰基异硫氰酸酯。
式(II)还包括由式(I)涵盖的任何化合物的一种或多种盐或溶剂化物。
在各种方面,本公开的方法另外包括向个体施用包含如式(III)中所示的式(I)的化合物的一种或多种组合物:
其中R3选自氢、烷基或芳基;且R4为芳基;其中,当R4为苯基时,R4被独立地选自烷基、支链烷基、杂烷基、环烷基、杂环烷基、卤基或芳基的0、1或2个基团取代;条件是当R4被杂烷基或杂环烷基取代时,这一个或多个杂原子不是S。所述化合物以有效抑制个体中胆碱向TMA的转化的量施用。在一些情况下,R3选自甲基、乙基、丙基、丁基、戊基、苯基或取代的苯基,诸如被1或2个选自甲基、乙基、丙基、丁基、烷氧基(例如,甲氧基、乙氧基)、烷硫基(例如,甲硫基、乙硫基)、氟、溴、氯、碘或(叔丁氧基羰基)氨基)的基团取代的苯基。在一些情况下,R4选自苯基或取代的苯基,诸如被1或2个选自甲基、乙基、丙基、丁基、烷氧基(例如,甲氧基、乙氧基)、烷硫基(例如,甲硫基、乙硫基)、氟、溴、氯、碘或(叔丁氧基羰基)氨基)的基团取代的苯基。
式(III)还包括由式(III)涵盖的任何化合物的一种或多种盐或溶剂化物。
“烷基”是指含有1至30个碳原子(即,C1-C30),例如1至20个碳原子(即,C1-C20)或1至10个碳原子(即,C1-C10)的直链和支链饱和烃基。在各种实施方案中,R2和R3的烷基基团独立地选自C1-C7烷基,即具有涵盖整个范围(即,1至7个碳原子)以及所有子组(例如,1-3、1-6、2-7、1-5、3-6、5-7、1、2、3、4、5、6和7个碳原子)的碳原子数目的烷基基团。烷基基团的非限制性示例包括甲基、乙基、正丙基、异丙基、正丁基、仲丁基(2-甲基丙基)、叔丁基(1,1-二甲基乙基)、3,3-二甲基戊基和2-乙基己基。除非另有指明,否则烷基基团可以是未取代的烷基基团或取代的烷基基团。烷基基团可以任选地被例如羟基(OH)、硫醇(SH)、芳基、杂芳基、环烷基、杂环基和氨基中的一个或多个取代。R2和/或R3可以包含杂烷基,条件是该杂原子不是硫。
术语“杂烷基”与烷基类似地定义,不同之处在于碳链含有1至3个杂原子,诸如独立地选自氧、氮或硫的杂原子。杂烷基的非限制性示例包括醚、酯、酮、伯胺、仲胺、叔胺和季胺、酰胺、巯基、烷基硫醚或氨基甲酸酯。除非另有指明,否则杂烷基基团可以是未取代的杂烷基基团或取代的杂烷基基团。
术语“环烷基”是指含有3至8个碳原子(例如,3-5、5-8、3、4、5、6、7或8个碳原子)的脂族环状烃基。环烷基基团的非限制性示例包括环丙基、环丁基、环戊基、环己基、环庚基和环辛基。除非另有指明,否则环烷基基团可以是未取代的环烷基基团或取代的环烷基基团。
术语“杂环烷基”与环烷基类似地定义,不同之处在于环含有1至3个独立地选自氧、氮或硫的杂原子的杂原子。杂环烷基基团的非限制性示例包括哌啶、四氢呋喃、四氢吡喃、4H-吡喃、二氢呋喃、吗啉、噻吩、1,4-二噁烷、呋喃、吡咯、吡咯烷、咪唑、吡唑、三唑、噻唑、吡嗪、吡喃、噁唑、噁嗪、噻嗪、嘧啶、哒嗪、硫胺等。环烷基和杂环烷基可以是任选被例如1至3个独立选择的烷基、亚烷基OH、C(O)NH2、NH2、氧代(=O)、芳基、卤代烷基、卤基和OH的基团取代的饱和或部分不饱和环系。杂环烷基基团任选地可以被烷基、羟烷基、亚烷基芳基和亚烷基杂芳基进一步N-取代。
术语“羟基(hydroxy)”或“羟基(hydroxyl)”是指“-OH”基团。术语“氨基”或“胺”是指-NH2或-NH-基团,其中每个式(I)、式(II)或式(III)中的每个氢都可以被烷基、环烷基、芳基、杂芳基或杂环烷基基团置换。“胺”包括任选被一个或多个另外的杂原子取代的环胺。术语“羧基(carboxy)”或“羧基(carboxyl)”是指“-COOH”基团。术语“硫醇”或“巯基”是指“-SH”基团。术语“氰基”是指-C≡N基团,也被称为-CN。术语“异氰酸基”是指-N≡C基团。术语“异氰基”是指-N=C=O基团。术语“异硫氰基”是指-N=C=S基团。术语“硝基”是指-NO2基团。
“取代的”烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基或烷氧基是指具有至少一个被非氢基(即,取代基)取代的氢基的烷基、烯基、炔基、环烷基、环烯基、芳基、杂芳基或烷氧基。非氢基(或取代基)的示例包括但不限于烷基、环烷基、烯基、环烯基、炔基、醚、芳基、杂芳基、杂环烷基、羟基、氧基(或氧代)、烷氧基、酯、硫酯、酰基、羧基、氰基、硝基、氨基、酰氨基或硫。当取代的烷基基团包含多于一个非氢基时,取代基可以与同一个碳或两个或更多个不同的碳原子键合。
如前所述,预期所公开的化合物的盐或溶剂化物,例如生理学上可接受的盐,并其任选地通过使适当的碱或酸与化学计量当量的化合物反应来制备。通常用于形成生理学上可接受的盐的酸包括无机酸,诸如二硫化氢、盐酸、氢溴酸、氢碘酸、硫酸和磷酸,以及有机单-、二和三酸,诸如对甲苯磺酸、水杨酸、酒石酸、二酒石酸、抗坏血酸、马来酸、苯磺酸、富马酸、葡糖酸、葡糖醛酸、甲酸、谷氨酸、甲磺酸、乙磺酸、苯磺酸、乳酸、草酸、对溴苯磺酸、碳酸、琥珀酸、柠檬酸、苯甲酸和乙酸,以及相关的无机酸和有机酸。生理学上可接受的盐包括硫酸盐、焦硫酸盐、硫酸氢盐、亚硫酸盐、亚硫酸氢盐、磷酸盐、磷酸一氢盐、磷酸二氢盐、偏磷酸盐、焦磷酸盐、氯化物、溴化物、碘化物、三氟甲烷磺酸盐(或三氟甲磺酸盐)、乙酸盐、丙酸盐、癸酸盐、辛酸盐、丙烯酸盐、甲酸盐、异丁酸盐、癸酸盐、庚酸盐、丙炔酸盐、草酸盐、丙二酸盐、琥珀酸盐、辛二酸盐、癸二酸盐、富马酸盐、马来酸盐、丁炔-1,4-二酸盐、己炔-1,6-二酸盐、苯甲酸盐、氯苯甲酸盐、甲基苯甲酸盐、二硝基苯甲酸盐、羟基苯甲酸盐、甲氧基苯甲酸盐、邻苯二甲酸盐、对苯二甲酸盐、磺酸盐、二甲苯磺酸盐、苯乙酸盐、苯丙酸盐、苯基丁酸盐、柠檬酸盐、乳酸盐、O-羟基丁酸盐、乙醇酸盐、马来酸盐、酒石酸盐、甲磺酸盐、丙磺酸盐、萘-1-磺酸盐、萘-2-磺酸盐、扁桃酸盐及其它盐。生理学上可接受的酸加成盐包括例如用无机酸如盐酸和氢溴酸形成的盐以及用有机酸如马来酸形成的盐。
生理学上可接受的碱加成盐可以用金属或胺如碱金属和碱土金属或有机胺形成。化合物的生理学上可接受的盐也可以用生理学上可接受的阳离子来制备。合适的生理学上可接受的阳离子在本领域中是公知的,并且包括但不限于碱金属、碱土金属、铵和季铵阳离子。碳酸盐或碳酸氢盐也是这方面的选择。用作阳离子的金属的示例是钠、钾、镁、铵、钙、铁等。合适的胺的示例包括但不限于异丙胺、组氨酸、N,N'-二苄基乙二胺、氯普鲁卡因、二乙醇胺、二环己胺、乙二胺、N-甲基葡糖胺和普鲁卡因。
在本发明的一些方面,所述化合物在十字花科蔬菜(例如,西兰花)中不是天然存在的。
在各种实施方案中,式(I)、式(II)或式(III)的化合物展示出1×10-3或更低、5×10-3或更低、1×10-4或更低、5×10-4或更低、1×10-5或更低、5×10-5或更低、或1×10-6或更低、或1×10-6和1×10-3之间、1×10-6和1×10-4之间、1×10-6和1×10-5之间、1×10-5和1×10-3之间、或1×10-4和1×10-3之间的IC50(观察到对由胆碱形成TMA(或TMAO)的50%抑制;mol/L),任选地在实施例中描述的测定中。
方法
本发明包括抑制个体中胆碱向三甲胺(TMA)的转化的一种或多种方法,其包括向所述个体施用包含如上文在子标题“化合物”下所述的式(I)、式(II)或式(III)中所示的化合物的一种或多种组合物。本文所述的任何实施方案的个体是需要降低TMA水平、改善心血管健康等的哺乳动物,优选人类,例如人类。在某些实施方案中,个体可以在施用之前表现出升高水平的TMA或其代谢物(例如,TMAO、二甲胺(DMA)或甲胺(MA,也称为单甲胺或MMA))。在各种实施方案中,个体患有心血管疾病,摄入高胆碱饮食,或表现出一种或多种CVD风险因素(例如,吸烟、压力、高总胆固醇、高LDL胆固醇、低HDL胆固醇、年龄、高血压、家族心血管病史、肥胖症、前驱糖尿病和/或糖尿病)。
还预期体外抑制胆碱向TMA的转化的一种或多种方法。就此而言,一种方法包括使细菌(例如,肠道微生物群中表现的细菌或代谢胆碱以产生TMA的细菌溶胞产物与如上文在子标题“化合物”下所述的式(I)的化合物接触)。在各种实施方案中,所述细菌选自奇异变形杆菌(Proteus mirabilis)、脱硫弧菌(Desulfovibrio alaskensis)、杨氏梭菌(Clostridium ljungdahlii)、梭状芽孢杆菌(C.scindens)、C.aldenense、Collinsellatanakaei、阴道厌氧球菌(Anaerococcus vaginalis)、停乳链球菌(Streptococcusdysgalactiae)、哈氏溃疡菌(Desultitobacterium hafniense)、变栖克雷伯氏菌(Klebsiella variicola)、克雷伯氏杆菌(K.pneumonia)、大肠杆菌或它们的组合。本公开还提供鉴定抑制TMA产生的化合物的一种或多种方法。一种方法包括使细菌(例如,作为肠道微生物群的一部分的细菌)或代谢胆碱以产生TMA的细菌溶胞产物与候选化合物(例如,如上文在子标题“化合物”下所述的式(I)、式(II)或式(III)的化合物)接触和检测TMA(或其代谢物)。任选地,将由与候选化合物接触的细菌产生的TMA(或其代谢物)的水平与(a)未与候选化合物或已知TMA抑制剂接触的细菌或溶胞产物产生的TMA水平或(b)与候选化合物接触之前的细菌产生的TMA水平相比较。由细菌产生的TMA水平的降低指示候选化合物抑制胆碱向TMA的转化。
还预期体外抑制胆碱向TMA的转化的一种或多种方法。一种方法包括使细菌或细菌溶胞产物与式(I)、式(II)或式(III)的一种或多种化合物接触。在各种实施方案中,所述细菌包括单一细菌物种或菌株,或者包含两种或更多种(例如,三种、四种、五种或更多种)不同细菌物种或细菌菌株的混合物。类似地,细菌溶胞产物由单一细菌物种或菌株或两种或更多种(例如,三种、四种、五种或更多种)不同细菌物种或细菌菌株的混合物产生。
应该理解,“抑制胆碱向TMA的转化”不需要通过胆碱代谢完全消除TMA的产生。预期由胆碱或胆碱相关代谢物作为前体形成TMA方面的任何降低,例如降低至少1%、至少5%、至少10%、至少15%、至少20%、至少25%、至少30%、至少35%、至少40%、至少45%、至少50%、至少55%、至少60%、至少65%、至少70%、至少75%至少80%、至少85%、至少90%、至少95%或100%;或约1%至约100%、约10%至约90%、约20%至约80%、约30%至约70%、约40%至约60%;或者更窄并且落入此类更宽数值范围内的任何其它数值范围,如同此类更窄的数值范围全部在本文中明确地写出。
用于体外或体内测量TMA的任何合适的方法可以用于本发明的上下文中。可以定量或定性地评估TMA、TMA的代谢物(例如,TMAO、DMA或MA)、TMA的稳定同位素(例如,氘标记的TMA,诸如d3-TMA、d6-TMA或d9-TMA)、TMAO的稳定同位素(例如,氘标记的TMAO,诸如d3-TMAO、d6-TMAO或d9-TMAO)、DMA的稳定同位素(例如,氘标记的DMA,诸如d3-DMA或d6-DMA)、MA的稳定同位素(例如,氘标记的MA,诸如d3-MA)和/或胆碱(包括胆碱的稳定同位素,例如d9-胆碱)。检测和定量TMA的示例性方法描述在例如美国公告2010/00285517中,其公开内容通过引用整体并入本文。例如,TMA(或三甲胺-N-氧化物(TMAO)、DMA或MA)和/或胆碱的水平任选通过质谱法、紫外光谱法或核磁共振光谱法测量。质谱仪包括电离源(例如,电喷雾电离)、根据质荷(m/z)比分离电离源中形成的离子的分析仪、以及用于带电离子的检测器。在串联质谱法中,包括两个或更多个分析仪。这类方法在本领域中是标准的并且包括例如具有在线电喷雾电离(ESI)和串联质谱的HPLC。
在各种实施方案中,在来自个体的生物样品中测量TMA和/或TMAO。生物样品包括但不限于全血、血浆、血清、尿液、粪便、唾液、汗液和/或组织。样品可以使用任何临床上可接受的实践来收集,并且如果需要,则在适当的缓冲溶液中稀释,肝素化,浓缩或分馏。可以使用许多生理学pH下的许多水性缓冲溶液中的任一种,诸如磷酸盐、Tris等。也可以使用酸化的缓冲液。例如,向样品添加缓冲液后的最终pH值任选地在pH 1和pH 6之间,例如在pH1.5和pH 3.0之间。
任选地,将生物样品中的TMA(或其代谢物或稳定同位素)和/或胆碱的水平与对照值相比较。所用的对照值将取决于本发明的实施方案。在一个方面,对照值是在施用或暴露于式(I)、式(II)或式(III)的化合物之前在个体中(或通过细菌)产生的TMA和/或TMAO的水平。或者,对照值基于从参考群体(例如,普通人群、诊断患有CVD或其它TMA相关病况的个体、先前未诊断为TMA相关病况的个体、非吸烟者等)获得的可相比的样品中测量的水平。TMA和/或TMAO和/或胆碱的水平可以与单个对照值或一系列对照值相比较。通过将来自个体的生物样品中的TMA的量与对照值相比较,可以将个体鉴定为在施用之前具有增强或升高的TMA水平。
本发明还提供改善个体的心血管健康的一种或多种方法。一种方法包括向所述个体施用包含以有效改善心血管健康的量的如上文在子标题“化合物”下所述的如式(I)、式(II)或式(III)中所示的化合物的一种或多种组合物。通过测试动脉弹性、血压、踝/臂指数、心电图、心室超声、血小板功能(即,血小板聚集)和血/尿测试来评估心血管健康,以测量例如胆固醇、白蛋白排泄、C-反应蛋白或血浆B-型肽(BNP)浓度。在本发明的各种方面,式(I)、式(II)或式(III)的化合物的施用改善或维持测定结果中的一种或多种测定结果在正常范围内。每个测试的结果的正常范围在本领域中是已知的。在一些实施方案中,心血管健康的改善以循环总胆固醇水平降低、循环低密度脂蛋白(LDL)降低、循环甘油三酯降低和/或血压降低为特征。
本发明还包括改善有此需要的个体中与胆碱向三甲胺(TMA)的转化相关的病况的一种或多种方法。一种方法包括向所述个体施用包含以有效改善所述病况的量的如上文在子标题“化合物”下所述的式(I)、式(II)或式(III)的化合物的一种或多种组合物。“改善病况”是指在与至少部分地由TMA引起的病症相关的症状的严重程度和/或发作方面的任何降低。本领域普通技术人员将理解,TMA有关的病症或与其相关的症状的任何程度的保护或改善对诸如人类的个体是有益的。通过降低个体中症状的严重程度和/或延缓症状出现改善个体的生活质量。因此,一方面,在确定个体处于发展TMA有关的病症的风险中之后或在检测到TMA有关的病症之后尽可能尽快地执行的一种方法。
在本发明的各种方面,与胆碱向三甲胺的转化相关的病况是心血管疾病、肾功能降低或受损、慢性肾病、三甲基胺尿症或糖尿病。术语“心血管疾病”(CVD)在本领域中用于提到影响身体的心脏、心脏瓣膜和脉管系统(例如,动脉和静脉)的病况,并且涵盖包括但不限于下列的疾病和疾病:动脉硬化、动脉粥样硬化、心肌梗塞、急性冠脉综合征、心绞痛、充血性心力衰竭、主动脉瘤、主动脉夹层、髂动脉或股动脉瘤、肺动脉栓塞、原发性高血压、心房颤动、中风、短暂性脑缺血发作、收缩功能障碍、舒张功能障碍、心房颤动、心内膜炎、动脉病、血管炎、动脉粥样硬化斑块、易损斑块、急性冠脉综合征、急性缺血发作、心脏性猝死、外周血管疾病、冠状动脉疾病(CAD)、外周动脉疾病(PAD)和脑血管疾病。
一方面,所述病况是动脉粥样硬化。动脉粥样硬化涉及动脉粥样硬化斑块的形成,其导致血管狭窄(“狭窄”),这最终可能导致血管的部分或完全闭塞或破裂(动脉瘤)、心力衰竭、主动脉夹层和心肌缺血事件如心肌梗塞和中风。在各种非限制性实施方案中,本发明的方法抑制、降低或逆转(全部或部分地)动脉粥样硬化的发作或发展(例如,降低或防止动脉硬化或增厚、斑块形成、内皮损伤和/或动脉炎症)。
在各种实施方案中,式(I)、式(II)或式(III)的化合物的施用引起TMA和/或TMAO水平降低、总胆固醇水平降低、LDL水平降低、HDL水平升高、甘油三酯水平降低和/或与CVD相关的其它生物标志物(例如,排泄的白蛋白、C-反应蛋白或血浆B-型肽(BNP))的水平正常化。在一些实施方案中,当施用给个体时,式(I)、式(II)或式(III)的化合物降低心血管疾病、肾功能降低或受损、慢性肾病、三甲基胺尿症或糖尿病的风险。
施用方案和组合物
施用给个体的化合物的量足以抑制(全部或部分地)由胆碱形成TMA。在本公开的各种方面,所述量改善心血管健康和/或相对于与TMA相关的不希望的病况实现有益的生物应答(例如,所述量足以改善,减缓进展或预防病况(例如,CVD))。有益效果可以通过例如临床病况的改善、症状的减轻或通过本文所述的任何测定或临床诊断测试来检测。个体的确切有效量可以取决于个体的体重、身材和健康;病况的性质和程度;以及选择施用的化合物或试剂组合。在各种方面,施用给个体的化合物的量为约0.001mg/kg至约1000mg/kg。以mg/kg计的特定剂量范围包括约0.1mg/kg至约500mg/kg,约0.5mg/kg至约200mg/kg,约1mg/kg至约100mg/kg,约2mg/kg至约50mg/kg,以及约5mg/kg至约30mg/kg。有效量可以作为化合物的单次施用或作为分次剂量(即,同时或在接近的时间以多个亚单位施用的单剂量)施用给个体。一定量的化合物任选地每天递送一次、两次或三次;每周一次、两次或三次;或者每月一次、两次、三次或四次。所述化合物可以作为在体外或体内转化成活性药物的前药递送。
所述化合物或包含所述化合物的组合物通过允许抑制胆碱向TMA的转化的任何途径来施用。在本发明的各种方面,所述化合物或包含所述化合物的组合物肠胃外(例如,静脉内、腹膜内、肺内、皮下或肌内)、鞘内、局部、透皮、直肠、口服、舌下、鼻内或通过吸入递送到个体。在各种优选的实施方案中,化合物通过例如摄取施用到胃肠道。当与胃肠道中的体液接触时,也可以采用持续释放制剂来实现化合物的受控释放。持续释放制剂在本领域中是已知的,并且通常包含生物可降解聚合物的聚合物基质、水溶性聚合物或两者的混合物,任选地还有合适的表面活性剂。
本发明提供包含用一种或多种生理学上可接受的赋形剂、载剂、稳定剂或稀释剂配制以便在本文所述的方法中使用的式(I)、式(II)或式(III)的化合物的一种或多种组合物。赋形剂包括但不限于载剂分子,其包括大的缓慢代谢的大分子,诸如蛋白质、多糖、聚乳酸、聚乙醇酸、聚合氨基酸、氨基酸共聚物、抗氧化剂(例如,抗坏血酸)、螯合剂(例如,EDTA)、碳水化合物(例如,糊精、羟烷基纤维素和/或羟烷基甲基纤维素)、脂质体、硬脂酸、液体(例如,油、水、盐水、甘油和/或乙醇)、润湿剂或乳化剂、pH缓冲物质等。
用于例如肠胃外或口服施用的制剂通常为固体(例如,冻干粉末或蛋糕)、液体溶液、乳剂或混悬剂,而用于肺部施用的可吸入制剂通常为液体或粉剂。示例性剂型包括但不限于片剂、糖锭剂、锭剂、水或油混悬剂、非水溶液、粉剂、可分散粉剂或颗粒剂(包括微粒化粒子或纳米粒子)、乳剂、硬或软胶囊、硬或软液体填充的胶囊、明胶胶囊、糖浆剂和酏剂。固体剂量制剂如片剂或液体填充的胶囊可以是未包衣的,或者可以通过包括微胶囊的已知技术包衣以延迟在胃肠道中的崩解和吸收。固体剂量制剂可以被包衣以靶向递送至消化道的特定区域。例如,所述制剂可以被肠溶包衣以将制剂靶向递送至小肠、大肠或结肠。另外的示例性剂型可以包含悬浮液或液体基体中的包衣的微胶囊或包衣的微珠。在一些实施方案中,式(I)、式(II)或式(III)的化合物作为饮食(例如,食物或饮品)补充剂提供。饮食补充剂是口服给药的,并且通常包含维生素、矿物质、草药或其它植物成分、氨基酸、酶、器官组织、来自腺体的组织或代谢物。在一个实施例中,式(I)、式(II)或式(III)的化合物作为条形食物提供。
在一些实施方案中,本文所述的化合物在适合低溶解度化合物的基于脂质的制剂中配制成口服施用。基于脂质的制剂通常可以增强这类化合物的口服生物利用度。因此,在一些方面,所述组合物包含一定量的本文所述的化合物以及至少一种选自中链脂肪酸及其丙二醇酯的赋形剂(例如,可食用脂肪酸的丙二醇酯,诸如辛酸和癸酸脂肪酸)和生理学上可接受的表面活性剂如聚氧乙烯40氢化蓖麻油。
在一些实施方案中,本文所述的化合物以延迟释放制剂的形式提供,并且任选地在个体的消化道的特定区域中释放。例如,可以提供制剂,使得化合物在消化道的远侧部分如回肠或结肠中自口服制剂释放。在某些实施方案中,延迟释放制剂在特定pH下或在一定pH范围内释放化合物,以在个体的消化道内靶向递送。所述化合物可以例如在pH 6.0和pH9.0之间、pH 6.5和pH 8.0之间、pH 6.5和pH 7.5之间、pH 7.0和pH 7.5之间、或者pH 7.0和pH 8.0之间释放。
本发明的方法任选地包括向个体施用第二试剂。术语“第二试剂”仅用于将所述试剂与式(I)、式(II)或式(III)的化合物加以区分,并不意味着限制在方法中使用的另外试剂的数量或表示施用顺序。一种或多种第二试剂任选地掺入具有同时施用但以分开的剂型或者在时间上分开施用的式(I)、式(II)或式(III)的化合物的组合物中。
示例性的第二试剂包括但不限于抗微生物剂(诸如杀死肠中细菌的抗生素);改善肠运动的试剂(诸如纤维或车前草);进一步降低肠中TMA水平的试剂,包括螯合剂(诸如活性木炭或铜叶绿酸;和/或进一步降低TMA代谢物产生的试剂;以及改善心血管健康的一个或多个方面的试剂,诸如使血压正常化、减少血管炎症、降低血小板活化、使脂质异常正常化的试剂。在各种实施方案中,第二试剂选自Omega 3油、水杨酸(阿司匹林)、二甲基丁醇、大蒜油、橄榄油、磷虾油、Co酶Q-10、益生菌、益生元、饮食纤维、蚤草壳、铋盐、植物甾醇、葡萄籽油、绿茶提取物、维生素D、抗氧化剂(诸如维生素C和维生素E)、姜黄、姜黄素、白藜芦醇、活性木炭或铜叶绿素。任选地,所述组合物包含二甲基丁醇和/或由胆碱以外的前体(例如肉碱)形成TMA的抑制剂。
或者或此外,本公开的方法还包括施用一种或多种心血管疾病疗法。疗法的示例包括但不限于他汀类(例如,LipitorTM(阿托伐他汀(atorvastatin))、PravacholTM(普伐他汀(pravastatin))、ZocorTM(辛伐他汀(simvastatin))、MevacorTM(洛伐他汀(lovastatin))和LescolTM(氟伐他汀(fluvastatin)))或干扰HMGCoA还原酶的活性的其它试剂;烟酸(尼克酸(niacin),其降低LDL胆固醇水平);贝特类(其降低血液甘油三酯水平并且包括例如苯扎贝特(Bezafibrate)(例如)、环丙贝特(Ciprofibrate)(例如)、氯贝丁酯(Clofibrate)、吉非贝齐(Gemfibrozil)(例如,)和非诺贝特(Fenofibrate)(例如,));胆汁酸树脂(例如考来烯胺(Cholestyramine)、考来替泊(Colestipol)(Colestip)和Cholsevelam(Welchol));胆固醇吸收抑制剂(例如,依替米贝(Ezetimibe));植物甾醇(例如,谷甾醇(sitosterol)(Take Control(Lipton));谷甾烷醇(sitostanol)(Benechol)或豆甾烷醇(stigmastanol));藻酸盐和果胶;卵磷脂和营养制品(例如,绿茶提取物和其它提取物,所述提取物包括多酚,特别是表没食子儿茶素没食子酸酯(EGCG)、Cholest-ArrestTM(500mg大蒜和200mg卵磷脂)、CholestawayTM(700mg碳酸钙、170mg氧化镁、50μg吡啶甲酸铬)、Cholest-OffTM(900mg植物甾醇/甾烷醇)、Guggul Bolic(750mg古古脂(印度穆库尔没药胶树脂)和(600mg老龄大蒜提取物和380mg卵磷脂))。
在前述实施方案的相关变体中,包含单独或与一种或多种第二试剂组合的本文所述的式(I)、式(II)或式(III)的化合物的一种或多种组合物任选地布置成试剂盒或包装或单位剂量,诸如容许共同施用多种试剂的试剂盒或包装或单位剂量。另一方面,包含式(I)、式(II)或式(III)的化合物和所述一种或多种第二试剂的组合物是混合物。在各种实施方案中,所述试剂盒或包装或单位剂量的一种或多种组分与关于施用这一种或多种组分到个体的说明书一起包装。
本发明的其它方面和优点将在考虑以下说明性实施例后理解,所述说明性实施例并非旨在以任何方式进行限制。
实施例
该实施例提供用于鉴定和表征抑制由胆碱形成TMA的化合物的示例性测定。
使奇异变形杆菌29906(Pm)菌株在500ml营养肉汤培养基(3g/L牛肉提取物,5g/L蛋白胨;Difco#234000)中在37℃下在250rpm振荡下有氧生长过夜。生物质通过在4℃以6000×g离心12分钟而沉淀。使细胞丸粒在240mL冰冷的1X磷酸盐缓冲盐水(不含Ca2+和Mg2 +)中悬浮。添加90微克溶菌酶(Sigma#L6876,批次#SLBG8654V)并在4℃下以320rpm振荡温育30分钟。溶胞是通过具有预冷却到4℃的直径为1"的腔室的法式滤压壶(French press)在1000psi(高比率;内部PSI相当于约16000)实现。将溶胞产物在4℃下以6,000×g离心12分钟以使额外的碎片粒化。离心的溶胞产物上清液的蛋白质浓度通过BCA蛋白质测定试剂盒(Pierce#23225)测定,并用1×杜氏磷酸盐缓冲盐水(DPBS)将蛋白质浓度调节至3mg/ml。将离心的上清液溶胞产物等分成20mL体积并在-80℃下冷冻储存。
奇异变形杆菌29906(Pm)溶胞产物用1×DPBS稀释至1.5mg/mL蛋白质。添加氯化胆碱(CC)(1M储备液)以达到2.5mM氯化胆碱的最终浓度。混合物使用涡旋混合器混合约15秒,并在37℃下温育22小时。温育后,将150μL的CC处理的Pm溶胞产物分配到深孔板(聚丙烯,2mL体积,Corning Axygen目录#P-DW-20-C)中。以1:100稀释度添加来自表1(下文)的候选IC50化合物和载体对照物(DMSO或水的相应载体对照物)或对照化合物(IC50对照,8-喹啉半硫酸盐(Sigma目录#55100))(例如,每孔1.5μL)。将平板在平板振荡器上搅拌1分钟。向所有孔中添加d9-氯化胆碱(1.5μL,5mM)以达到50μM的最终d9-氯化胆碱浓度。
再次将平板在平板振荡器上搅拌1分钟,并在37℃下温育2小时。温育后,向每个孔中添加1.5μL甲酸(最终浓度=1%甲酸)。将平板在平板振荡器上搅拌1分钟并置于冰上。将细胞溶胞产物掺杂稳定同位素标记的内标(向每个样品中添加22.5μL的6μg/mL的13C3-三甲胺(13C3-TMA)),然后在如下所述的蛋白质沉淀之后从溶胞产物中分离d9-三甲胺(d9-TMA)、三甲胺(TMA)和13C3-TMA。将用0.1%甲酸酸化的乙腈(600μL)添加到每个样品中,然后将其离心(2100g,20分钟)以使蛋白质和其它沉淀物粒化。如下所述移出并分析上清液。分离的上清液样品中的TMA、d9-TMA和13C3-TMA在具有得自Waters Corp.,Milford,Mass.的Atlantis Silica HILIC Sentry保护管柱(3μm,2.1mm×10mm)的得自WatersCorp.,Milford,Mass.的Waters Atlantis HILIC Silica柱(2.1×50mm,3μm粒子)上进行梯度高效液相色谱(HPLC),其中具有0.1%甲酸的10mM甲酸铵水溶液作为流动相A且0.1%甲酸的乙腈溶液作为流动相B。检测和定量通过在多反应监测(MRM)MS/MS条件下操作的串联质谱法实现(TMA,m/z 44.1;d9-TMA,m/z 49.1;13C3-TMA,m/z 46.1)。使用在80%/20%/0.1%乙腈/水/甲酸中制备的TMA和d9-TMA校准标准物(STD)通过绘制每种标准物的应答(峰面积TMA/峰面积13C3-TMA)对浓度构建回归曲线。通过二次(1/x2)回归曲线插值确定细胞溶胞产物中TMA和d9-TMA的浓度。
式(I)的代表性化合物的IC50测量值示于表1中。
表1
该实施例提供鉴定和定量样品中的TMA以及筛选候选抑制化合物的示例性方法。发现表1中的所有化合物均抑制胆碱向TMA的转化。
本文所公开的量纲和值不应理解为严格限于所引用的精确数值。相反,除非另外指明,否则每个这样的量纲旨在表示所述值以及围绕该值功能上等同的范围。例如,公开为“40mm”的量纲旨在表示“约40mm”。
除非明确排除或以其它方式限制,本文中引用的每一篇文献,包括任何交叉引用或相关专利或专利申请以及本申请对其要求优先权或其有益效果的任何专利申请或专利,均据此全文以引用方式并入本文。任何文献的引用不是对其作为与本发明任何公开或本文受权利要求书保护的现有技术的认可,或不是对其自身或与任何其它参考文献或多个参考文献的组合提出、建议或公开了此发明任何方面的认可。此外,当本发明中术语的任何含义或定义与以引用方式并入的文件中相同术语的任何含义或定义矛盾时,应当服从在本发明中赋予该术语的含义或定义。
虽然已举例说明和描述了本发明的具体实施方案,但是对于本领域技术人员来说显而易见的是,在不脱离本发明的实质和范围的情况下可作出多个其它变化和修改。因此,本文旨在于所附权利要求中涵盖属于本发明范围内的所有这些变化和修改。
Claims (7)
1.一种通过细菌来抑制胆碱向三甲胺(TMA)的转化的方法,所述方法包括:使所述细菌与如式(I)中所示的化合物接触:
其中R1选自氰酸酯、异氰酸酯、硫氰酸酯、异硫氰酸酯、腈、异腈或巯基;
n’选自0、1、2、3、4、5、6、7、8、9或10;并且
R2选自烷基、支链烷基、杂烷基、环烷基、杂环烷基、芳基或取代的羰基;
其中当R2为苯基时,R2被独立地选自烷基、支链烷基、杂烷基、环烷基、杂环烷基、卤基或芳基的0、1或2个基团取代;
其中当R2为杂烷基或杂环烷基时,一个或多个杂原子不是S;
其中当n'为2时,R2不是未取代的苯基;以及
包括其任何可接受的盐或溶剂化物。
2.根据权利要求1所述的方法,其中R1为异硫氰酸酯,优选地其中所述化合物为异硫氰酸仲丁酯或异硫氰酸乙酯。
3.根据权利要求2所述的方法,其中n'为0,优选地其中所述化合物选自异硫氰酸苯甲酰酯、异硫氰酸4-溴苯酯、异硫氰酸4-(甲硫基)苯酯、异硫氰酸1-萘酯、异硫氰酸3-甲氧基苯酯和异硫氰酸4-甲氧基苯酯。
4.根据权利要求2所述的方法,其中n'为至少1,优选地其中所述化合物为以下中的至少一种:异硫氰酸苄酯、异硫氰酸3-二乙氨基丙酯、N-Boc-4-异硫氰酸根合丁胺、异硫氰酸3-(4-吗啉代)丙酯、异硫氰酸2-(4-吗啉代)乙酯和异硫氰酸2-哌啶代乙酯。
5.根据权利要求1至4中任一项所述的方法,所述方法还包括使所述细菌与第二试剂接触,所述第二试剂为以下中的至少一种:Omega 3油、水杨酸、二甲基丁醇、大蒜油、橄榄油、磷虾油、Co酶Q-10、益生菌、益生元、饮食纤维、蚤草壳、铋盐、植物甾醇、葡萄籽油、绿茶提取物、维生素D、抗氧化剂、姜黄、姜黄素、白藜芦醇、活性木炭或铜叶绿素。
6.根据权利要求1至5中任一项所述的方法,其中胆碱向三甲胺(TMA)的转化被抑制约1%至约100%。
7.根据权利要求1至6中任一项所述的方法,其中所述细菌为以下中的至少一种:奇异变形杆菌、脱硫弧菌、杨氏梭菌、梭状芽孢杆菌、C.aldenense、Collinsella tanakaei、阴道厌氧球菌、停乳链球菌、哈氏溃疡菌、变栖克雷伯氏菌、克雷伯氏杆菌或大肠杆菌。
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