CN116390732A - 作为肝x受体激动剂的桦褐孔菌醇及其用途 - Google Patents
作为肝x受体激动剂的桦褐孔菌醇及其用途 Download PDFInfo
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- CN116390732A CN116390732A CN202180054109.1A CN202180054109A CN116390732A CN 116390732 A CN116390732 A CN 116390732A CN 202180054109 A CN202180054109 A CN 202180054109A CN 116390732 A CN116390732 A CN 116390732A
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Abstract
本发明涉及一种作为肝X受体激动剂的桦褐孔菌醇及其治疗肝X受体介导的疾病的用途，根据本发明一个方面的桦褐孔菌醇及其前体药物对肝X受体β(LXRβ)具有特异性激动剂活性，因此，与其他肝X受体(LXRs)激动剂相比不仅具有显著的稳定性，而且具有可以有效用于治疗肝X受体(LX Rs)相关疾病的效果，例如，脑神经退行性疾病、自身免疫性疾病、非酒精性脂肪性肝炎(NASH)、非酒精性脂肪性肝病(NAFLD)等。
Description
技术领域
本发明涉及一种作为肝X受体激动剂的桦褐孔菌醇及其治疗肝X受体介导的疾病的用途。
背景技术
肝X受体(Liver-X receptors，LXRs)是一种配体激活的转录因子，其在调节参与脂质代谢和细胞胆固醇稳态的基因表达方面发挥重要作用。肝X受体(LXRs)激动剂已被证明可以增强使胆固醇从肝脏外周逆向转运回肝脏进行处理和排泄的胆固醇逆向转运(enhanced reverse cholesterol transport，RCT)。胆固醇逆向转运(RCT)通过向上调节外周吞噬细胞中的胆固醇转运蛋白(ATP结合盒：ABCA1和ABCG1)而发生。据报告，激活胆固醇逆向转运(RCT)可以抑制动脉粥样硬化(atherosclerosis)的进展。
肝X受体(LXR)有根据不同的基因编码的两种同源异构体(isofor m)，即LXRα(NR1H3)和LXRβ(NR1H2)。LXRβ通常在大多数组织中表达，相反，LXRα表达具有组织选择性，并且在对脂质稳态重要的肝脏、小肠、肾脏、脂肪组织和肾上腺中表达。这两个肝X受体(LXRs)作为为了协同识别或结合肝X受体应答元件(LXRs response elements，LXREs)的强制性异二聚体伴侣(heterodimer partner)，需要视黄醛X受体(retinoid-X re ceptor，RXR)，其中，所述肝X受体应答元件(LXRs response elements，LXREs)是由两个被四个核苷酸(DR4)分隔的核心六聚体序列(core hexam eric sequence)的直接重复构成。所述两个肝X受体(LXRs)的配体结合域可以保存得相当良好(～78％的氨基酸同源性)，并且与内源性配体(endoge nous ligands)相结合，其中，所述内源性配体由在类固醇激素和胆汁酸合成中起到中间体作用的胆固醇氧化衍生物(氧化型胆固醇；oxysterols)组成。其中，已有报告指出22(R)-羟基胆固醇(hydroxycholesterol)、24(S)-羟基胆固醇(hydroxycholesterol)和24(S),25-环氧胆固醇(epoxycholesterol)为能力最强的配体。这些数据表明肝X受体(LXRs)可能在维持胆固醇稳态方面存在发挥重要作用的可能性，并且之后通过对小鼠进行的基因敲除(knock-out)研究证实了这一作用。至今为止非甾体配体(Non-steroidal ligands)已经被证实，并且通过将其用作化学探针(probe)，发现了许多肝X受体(LXRs)调节基因。含有多种肝X受体应答元件(LXRE)的基因参与胆固醇代谢、胆固醇逆向转运(RCT)和脂肪生成。其他基因参与炎症和碳水化合物代谢缺陷肝X受体应答元件(LXREs)，但是在配体依赖性方式方面被肝X受体(LXRs)抑制。基于这些发现，最近出现了所述肝X受体，其作为充当细胞内胆固醇传感器的极好靶标(target)，为治疗包括动脉粥样硬化、糖尿病、阿尔茨海默病、皮肤病、生殖疾病和癌症等各种疾病提供了基础(Viennoisetal.，2011，Expert Opin.Ther.Targets,15(2):219-232)。此外，已发现肝X受体(LXRs)激动剂依次调节肠内和肾脏磷酸钠(NaPi)转运蛋白和血清磷酸盐浓度(Caldas etal.，2011，Kidney International,80:535-544)。因此，肝X受体(LXR)也可以成为用于预防肾脏疾病的靶标(target)，特别是高磷血症及相关心血管并发症。此外，肝X受体(LXRs)被认为是治疗骨质疏松症及其相关疾病的靶标(Kleyer et al.,2012,J.Bone Miner.Res.,27(12):24451)。
阿尔茨海默病作为最常见的痴呆症的一种形式，其特征是大脑中β-淀粉样蛋白肽(amyloid-beta(Aβ)peptides)的积累和沉积，并且患病的个人大脑中接连出现神经接合功能的扰动和神经元丢失。神经元通过脑内淀粉样前体蛋白(amyloid precursor protein，APP)的裂解产生β-淀粉样蛋白肽myloid-beta(Aβ)peptides)，并且β-淀粉样蛋白肽(amyloid-beta(Aβ)peptid es)通常通过流出到末梢循环和脑内蛋白分解酶的作用而被消除。
载脂蛋白E(Apolipoprotein E，apoE)在阿尔茨海默病中与年龄有关的风险相关，并且在β-淀粉样蛋白肽(Aβ)稳态中起着关键作用。肝X受体(LXR)增加载脂蛋白E(apoE)的表达，并且增加载脂蛋白E(apoE)的脂质结合。β-淀粉样蛋白肽(Aβ)的降低无论是在细胞内还是细胞外都是根据脂化载脂蛋白E(apoE)增强。肝X受体(LXRs)激动剂(agonist)治疗促进了β-淀粉样蛋白肽(Aβ)的蛋白水解降低，减少了斑块(plaque)疾病，并且增强了移植淀粉样前体蛋白(APP)表达基因的小鼠的记忆力(Jiang etal.,2008,Neuron,58:681-693)。
因此，有必要通过研发肝X受体(LXRs)激动剂来研发治疗动脉硬化、阿尔茨海默病和代谢性疾病等肝X受体(LXRs)介导相关疾病的方法。
发明内容
技术问题
本发明的一个方面是提供一种肝X受体(Liver-X receptors，LXRs)激动剂，其包括桦褐孔菌醇、其前体药物或其药学上可接受的盐作为活性成分。
本发明的另一个方面是提供一种用于预防或治疗肝X受体(Liver-Xreceptors，LXRs)介导的疾病的药物组合物，其包括桦褐孔菌醇(Inotodiol)、其前体药物或其药学上可接受的盐作为活性成分。
本发明的又一个方面是提供一种桦褐孔菌醇、其前体药物或其药学上可接受的盐用于制备肝X受体(Liver-X receptors，LXRs)激动剂、或肝X受体介导的疾病的治疗剂的用途。
本发明的又一个方面是提供一种向上调节肝X受体(Liver-X receptors，LXRs)的方法和治疗肝X受体介导的疾病的方法，其包括将桦褐孔菌醇、其前体药物或其药学上可接受的盐施用于需要其的个体。
本发明的又一个方面是提供一种用于预防或改善肝X受体(Liver-X receptors，LXRs)介导的疾病的保健品，其包括桦褐孔菌醇(Inotodiol)、其前体药物或其药学上可接受的盐作为活性成分。
本发明的又一个方面是提供一种用于预防或改善肝X受体(Liver-X receptors，LXRs)介导的皮肤状况的化妆品组合物，其包括桦褐孔菌醇(Ino todiol)、其前体药物或其药学上可接受的盐作为活性成分。
技术方案
本发明的一个方面提供一种肝X受体(Liver-X receptors，LXRs)激动剂，其包括桦褐孔菌醇、其前体药物或其药学上可接受的盐作为活性成分。
本发明的另一个方面提供一种用于预防或治疗肝X受体(Liver-X receptors，LXRs)介导的疾病的药物组合物，其包括桦褐孔菌醇(Inotodiol)、其前体药物或其药学上可接受的盐作为活性成分。
本发明的又一个方面提供一种桦褐孔菌醇、其前体药物或其药学上可接受的盐用于制备肝X受体(Liver-X receptors，LXRs)激动剂、或肝X受体介导的疾病的治疗剂的用途。
本发明的又一个方面提供一种向上调节肝X受体(Liver-X receptors，LXRs)的方法和治疗肝X受体介导的疾病的方法，其包括将桦褐孔菌醇、其前体药物或其药学上可接受的盐施用于需要其的个体。
如本文所用，“桦褐孔菌醇(Inotodiol)”具有的IUPAC名称是(3S,5R,10S,13R,14R,17R)-17-[(2S,3R)-3-羟基-6-甲基庚-5-烯-2-基]-4,4,10,13,14-五甲基-2,3,5,6,7,11,12,15,16,17-十氢-1H-环戊二烯并[a]菲-3-醇((3S,5R,10S,13R,14R,17R)-17-[(2S,3R)-3-hydroxy-6-methylhept-5-en-2-yl]-4,4,10,13,14-pentamethyl-2,3,5,6,7,11,12,15,16,17-decahydro-1H-cyclopenta[a]phenanthren-3-ol)。
所述桦褐孔菌醇作为桦树茸(Inonotus obliquus)的主要生理活性成分，可以按常规方法化学合成，并且可以制备成药学上可接受的盐，或可以从桦树茸提取物中分离、提纯。
所述桦褐孔菌醇或其前体药物作为肝X受体(LXRs)激动剂而发挥作用。
本文所提供的是治疗患有可以通过肝X受体(LXRs)激动剂治疗的疾病或障碍的受试者的方法。在一个实施例中，肝X受体(LXR)可以通过向上调节肝X受体(LXRs)活性来调节。所述方法由施用有效量的桦褐孔菌醇或其前体药物组成。
本文所提供的所述方法或药物组合物可以对可通过调节肝X受体(LX Rs)治疗的障碍，特别是在作为肝X受体(LXRs)激动剂(agonist)的情况下有效。
在一个实施例中，桦褐孔菌醇或其前体药物对治疗或预防胆固醇转运改变(altered cholesterol transport)、脂肪酸代谢、胆固醇吸收、胆固醇再吸收、胆固醇分泌、胆固醇排泄或与胆固醇代谢相关的疾病或障碍有效。具有代表性的疾病或障碍包括脂质紊乱；癌症，特别是包括卵巢癌、乳腺癌和前列腺癌的激素依赖性癌症；痤疮性皮肤状况；炎症性皮肤病；免疫障碍；以破坏表皮屏障功能为特征的状况；异常的分化(disturbeddifferentiation)或表皮或粘膜的过度扩散；心血管障碍；生殖道障碍；视神经和视网膜异常；疾病引起的神经退行性障碍；中枢或末梢神经系统损伤；神经病性疾病；或因老化而引起的退化过程；肾脏疾病或障碍；以及骨质疏松症及其相关的疾病，但不限于此。
在另一个实施例中，所述疾病或障碍是脑神经退行性疾病(neurodegenerativebrain disease)、自身免疫性疾病(Autoimmune disease)、高脂血症(hyperlipidemia)、高胆固醇血症(hypercholesterolemia)、高脂蛋白血症(hyperlipoproteinemia)、高三酰甘油血症(hypertriglyceridemia)、脂质营养不良(lipodystrophy)、肝脂肪变性(hepaticsteatosis)、非酒精性脂肪性肝炎(nonalcoholic steatohepatitis，NASH)、非酒精性脂肪性肝病(nonalcoholic fatty liver disease，NAFLD)、高血糖症(hyperglycemia)、胰岛素抵抗(insulin resistance)、糖尿病(diabetes mellitus)、血脂紊乱(dyslipidemia)、动脉粥样硬化(atherosclerosis)、胆结石(gallstone disease)、痤疮(acne vulgaris)、皮炎(dermatitis)(不限于银屑病(psoriasis)、接触性皮炎(contact dermatitis))、高磷血症(hyperphosphatemia)、高磷血症相关的心血管并发症(cardiovascular complicationsof hyperphosphatemia)、癌症(cancer)、多发性硬化(multiple sclerosis)、或骨质疏松症(osteoporosis)。
在另一个实施例中，所述疾病或障碍包括寻常痤疮(common acne)；粉刺(comedones)；多形体(polymorphs)；玫瑰痤疮(rosacea)；结节囊肿型痤疮(nodulocysticacne)；聚合性痤疮(acne conglobate)；老年性痤疮(senile acne)；继发性痤疮(secondary acne)，其包括但不限于日光性(solar)、药物性(medicinal)和职业性(occupational))痤疮；鱼鳞病(ichthyosis)；鳞癣状病症(ichthyosiform conditions)；毛囊角化病(Darier's disease)；掌跖角皮症(palmoplantar keratoderma)；黏膜白斑病(leukoplakia)；黏膜白斑病型病症(leukoplakiform conditions)；皮肤或黏膜(口部)苔癣病(cutaneous or mucous(oral)lichen)；包括湿疹(eczema)、呼吸道特异性反应(respiratory atopy)和牙龈肥大(gingival hypertrophy)，并具有炎症免疫过敏成分并伴有或不伴有细胞增殖障碍的皮肤状况或疼痛(dermatological conditions orafflictions with an inflammatory immunoallergic component,with or without acellular proliferation disorder)，其包括但不限于皮肤银屑病(cutaneouspsoriasis)、黏膜银屑病(mucous psoriasis)、指甲型银屑病(ungual psoriasis)、银屑风湿病(psoriatic rheumatism)、皮肤特异性反应(cutaneous atopy)；因病毒或非病毒产生的良性或恶性皮肤或表皮扩散，其包括但不限于寻常疣(common warts)、扁平疣(flatwarts)、疣状表皮发育不良(epidermodysplasia verruciformis)、口腔菜花状乳头瘤病(oral or florid papillomatoses)，以及T淋巴瘤或皮肤T细胞淋巴瘤(cutaneous T-celllymphoma)；因紫外线引起的扩散，其包括但不限于基底细胞上皮瘤(basocellularepithelioma)、棘细胞上皮瘤(spinocellular epithelioma)；癌前皮肤病变(precancerous skin lesions)，其包括但不限于角化棘皮瘤；免疫性皮炎(immunedermatitides)，其包括但不限于红斑狼疮(lupus erythematosus)；免疫性大疱病(bullous immune diseases)；胶原蛋白病(collagen diseases)，其包括但不限于硬皮病(scleroderma)；皮肤或全身状况或具有免疫性因素的病痛(afflictions with animmunological component)；由于暴露于紫外线(UV)辐射引起的皮肤障碍；日光导致的皮肤老化或慢性皮肤老化；光化色素(actinic pigmentations)；角化病(keratosis)；与年龄或光老化(chronological or actinic aging)相关的疾病，其包括但不限于老年性干燥症(xerosis)；皮脂功能障碍(sebaceous function disorders)，其包括但不限于脂溢性痤疮、单纯性皮脂溢出(simple seborrhea)和脂溢性皮炎(seborrhoeic dermatitis)；瘢痕形成异常(cicatrization disorders)，其包括但不限于妊娠纹(stretch marks)；色素沉着异常(pigmentation disorders)，其包括但不限于色素沉着过多(hyperpigmentation)、黑皮病(melasma)、色素沉着减少(hypopigmentation)和白癜风(vitiligo)；脱发症(alopecia)，其包括但不限于化疗相关性脱发和放疗相关性脱发。
在另一个实施例中，所述疾病或障碍是脑神经退行性疾病(neurodegenerativebrain disease)或自身免疫性疾病(Autoimmune disease)。
所述脑神经退行性疾病可以选自由痴呆症、阿尔茨海默病(Alzheimer'sdisease)、帕金森病、亨廷顿舞蹈症、轻度认知障碍(mild cognitive impairment)、脑淀粉样血管病、唐氏综合症、淀粉样变性脑卒中(stroke)、系统性淀粉样变性、荷兰(Dutch)型淀粉样变性、尼曼-
皮克病、老年性痴呆症、肌萎缩侧索硬化(amyotrophic lateral sclerosis)、脊髓小脑萎缩症(Spinocerebellar
Atrophy)、图雷特综合征(Tourette`s Syndrome)、弗里德赖希共济失调(Friedrich`s Ataxia)、马查多-约瑟夫病(Machado-Joseph`s disease)、路易体痴呆(Lewy Body Dementia)、肌张力障碍(Dystonia)、进行性核上性麻痹(ProgressiveSupranuclear Palsy)和额颞痴呆(Frontotemporal Dementia)组成的组。
所述自身免疫性疾病可以选自由类风湿性关节炎(Rheumatoid arthritis)、银屑病(psoriasis)、皮炎(dermatitis)、多发性硬化(multiple sclerosis)和糖尿病(diabetes mellitus)组成的组。所述皮炎可以包括特应性、痤疮性和接触性皮炎等。
本发明人已确认桦褐孔菌醇可以被有效地输送到动物的大脑，并且已确认其提高了已知作为消除大脑中的炎症和β-淀粉样蛋白的因子的ATP结合盒转运蛋白A1(ABCA1)和载脂蛋白E(APOE)基因的表达，因此已证实其可以有效用于预防或治疗脑神经退行性疾病。
此外，在关节炎动物模型中已确认桦褐孔菌醇具有缓解关节炎的效果，并且已确认其降低了肿瘤坏死因子-α(TNF-α)的表达，因此已证实其可以有效用于预防或治疗关节炎以及自身免疫性疾病，例如，银屑病和皮炎等。
在一个具体实施例中，桦褐孔菌醇的前体药物可以是如下式1所示的桦褐孔菌醇化合物的羟基与脂肪酸、葡糖醛酸(glucuronic acid)、烷基琥珀酐或酚酸的羧基通过酯缩合反应形成的桦褐孔菌醇酯衍生物化合物：
[式1]
具体而言，所述前体药物可以是由下式2表示的化合物：
[式2]
在所述式中，R1和R2彼此独立地为OH或-OC(O)-R3，R3是具有1个至30个、4个至30个或6个至30个碳原子数的直链或支链烷基、烯基或炔基，
并且R1和R2中至少有一个是-OC(O)-R3。
在一个具体实施例中，所述R3是具有CH3(CH2)a-或CH3(CH2)b(CH＝CH[CH2])c(CH2)d-的未取代的直链烷基或烯基，a是8至24的整数，b是1至5的整数，c是1至6的整数，d是3至7的整数。
如本文所用，术语“前体药物(Prodrug)”可以是指本身可能无生物学活性，但是其在体内停留期间发生化学/生化结构转变后显示出有效的药效的药物。换句话说，虽然它是一种有用的药物，但是可以对在副作用、稳定性、溶解性、吸收性和作用持续时间等具有不合适性质的方面进行化学修饰，从而使临床使用成为可能。根据一个具体实施例的桦褐孔菌醇衍生物作为通过桦褐孔菌醇和脂肪酸的酯键形成的化合物，除了对有机溶剂的溶解度和稳定性得到提高之外，还因在小肠中容易分解成桦褐孔菌醇和脂肪酸而容易被小肠吸收。例如，所述桦褐孔菌醇衍生物可以是通过桦褐孔菌醇和琥珀酸的酯键形成的化合物。具体而言，所述桦褐孔菌醇衍生物可以通过在存在对甲苯磺酸催化的情况下，使烷基琥珀酸酐和桦褐孔菌醇进行缩合反应来合成，并且加入比桦褐孔菌醇过量的烷基琥珀酸酐，可以诱导桦褐孔菌醇的全部或至少一个羟基上酯键结合琥珀酸。反应完成后，使用碳酸氢钠中和以除去对甲苯磺酸。根据所述方法合成的褐孔菌醇衍生物化合物中，所述式2中的全部或至少一个R1和R2形成琥珀酸酯键，从而提高了水溶性，并且由于酯键易分解而容易被小肠吸收。此外，根据另一个具体实施例的桦褐孔菌醇衍生物不仅通过桦褐孔菌醇和脂肪酸的酯键增加桦褐孔菌醇的水溶性，而且降低了在小肠内的水解和体内吸收程度，以提高桦褐孔菌醇衍生物到达大肠的概率，从而在桦褐孔菌醇衍生物被大肠中的各种微生物分解的情况下，可以使桦褐孔菌醇直接发挥药理作用。例如，所述桦褐孔菌醇衍生物可以是通过桦褐孔菌醇和酚酸的酯键形成的化合物。具体而言，所述桦褐孔菌醇衍生物的酯键在大肠中水解，以释放出桦褐孔菌醇和酚酸，因此可以期待桦褐孔菌醇和酚酸各自具有的多种生理活性。因此，根据本发明一个方面的前体药物不仅可以减少桦褐孔菌醇的剂量，而且可以减少以高浓度摄取时可能发生的副作用。
所述桦褐孔菌醇的前体药物衍生物可以通过化学或生物学方法合成。具体而言，所述桦褐孔菌醇衍生物可以根据桦褐孔菌醇和脂肪酸的酯化反应合成。所述脂肪酸可以是C10至C30不饱和或饱和脂肪酸，并且可以选自由C1至C10羧酸或酚酸组成的组。所述不饱和脂肪酸可以是例如，肉豆蔻烯酸、棕榈油酸、顺式-6-十六碳烯酸、油酸、反式油酸、异油酸、亚油酸、亚麻酸、花生四烯酸、二十碳五稀酸、芥酸和二十二碳六烯酸等。所述饱和脂肪酸可以是例如，辛酸、癸酸、月桂酸、棕榈酸、硬脂酸、花生酸、山萮酸、木蜡酸、蜡酸和肉豆蔻酸等。所述饱和羧酸可以是例如，甲酸(Formic acid)、乙酸(Acetic acid)、丙酸(Propionicacid)、丁酸(Butyric acid)和琥珀酸(succinic acid)等。所述酚酸可以是例如，对香豆酸(p-coumaric acid)、肉桂酸(cinnamic acid)、阿魏酸(ferulic acid)、3，4-二羟基苯甲酸(3,4dihydroxy benzoic acid)、对羟基苯甲酸(p-hydroxy benzoic acid)、香草酸(vanilic acid)、咖啡酸(caffeic acid)、丁香酸(syringic acid)、芥子酸(sinapinicacids)等。在一个具体实施例中，所述桦褐孔菌醇衍生物可通过以1：10至30的摩尔比混合桦褐孔菌醇和选自由不饱和脂肪酸、饱和脂肪酸和C1至C10羧酸组成的组中的脂肪酸来合成。例如，所述桦褐孔菌醇衍生物可以1：10至30、1：10至25、1：10至20、1：10至15、1：10至13、5：10至30或5：10至15的摩尔比混合而成。此时，当桦褐孔菌醇和脂肪酸的混合比小于或大于所述范围时，由于反应进行得不充分，导致桦褐孔菌醇衍生物的生成效率降低或反应所需时间增加的问题。此外，所述酯化反应可以是在55℃至65℃下反应48至96小时。此时，当酯化反应条件小于或大于所述范围时，由于作为反应底物的脂肪酸难以完全溶解，因此几乎不产生反应或酶活性降低，导致酯化反应效率降低，从而存在无法以高产率合成作为最终产物的桦褐孔菌醇衍生物的问题。此外，在所述酯化反应完成后，可以通过已知的各种蒸馏方法或提纯方法进一步提高产物中所含的酯的纯度。
此外，可以通过在所述桦褐孔菌醇和脂肪酸的混合物中加入生物酶进行合成，并且所述生物酶作为适合于制备高效的桦褐孔菌醇衍生物的酶，例如，可以是南极假丝酵母脂肪酶B(Candida Antarctica Lipase B,CalB)。为了提高作为最终产物的桦褐孔菌醇衍生物的产率，所述南极假丝酵母脂肪酶B可以使用固定化酶(immobilized enzyme)而不是普通酶，并且所述固定化酶可以使用市售产品，或可以使用通过常规方法制备的固定化酶。此外，基于100重量份的桦褐孔菌醇，可以加入400至500重量份的所述南极假丝酵母脂肪酶B以合成桦褐孔菌醇衍生物。此时，当南极假丝酵母脂肪酶B的含量小于所述范围时，由于酯化反应进行得不充分，存在产生酯的效率低的问题，而当其大于所述范围时，无法以高产率合成作为最终产物的桦褐孔菌醇衍生物，因此存在不经济实惠的问题。
根据本发明一个方面的药物组合物可以按照各个常规方法剂型化为散剂、颗粒剂、片剂、胶囊剂、悬浮液、乳剂、糖浆剂、气雾剂等口服剂型，也可以剂型化为外用剂、栓剂和无菌注射溶液形式使用，并且为了剂型化，可以包括常规用于制备药物组合物的合适的载体、赋形剂或稀释剂。
所述载体或赋形剂或稀释剂可以是包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、木糖醇、赤藓糖醇、麦芽糖醇、淀粉、阿拉伯树胶、褐藻酸盐、明胶、磷酸钙、硅酸三钙、纤维素、木质纤维素、微晶纤维素、聚乙烯吡咯烷酮、水、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石粉、硬脂酸镁和矿物油等的各种化合物或混合物。
当进行剂型化时，可以利用常用的填充剂、增重剂、结合剂、润湿剂、崩解剂、表面活性剂等稀释剂或赋形剂进行制备。
本发明的另一个方面提供一种用于预防或治疗肝X受体(Liver-Xreceptors，LXRs)介导的疾病的方法，其包括将桦褐孔菌醇(Inotodiol)、其前体药物或其药学上可接受的盐施用于需要其的个体。
本发明的又一个方面提供一种桦褐孔菌醇(Inotodiol)、其前体药物或其药学上可接受的盐在用于制备用于预防或治疗肝X受体(Liver-Xreceptors，LXRs)介导的疾病的组合物的用途。
所述肝X受体(Liver-X receptors，LXRs)介导的疾病如上所述。
本说明书提供了增加胆固醇逆向转运和/或抑制动脉粥样硬化进展和促进缓解动脉粥样硬化的方法。
本说明书提供一种治疗与需要提高高密度脂蛋白胆固醇(high densitylipoprotein(HDL)-cholesterol)水平相关的疾病或障碍的方法，其包括对有需要的哺乳动物(特别是人)施用有效量的桦褐孔菌醇或其前体药物。
本说明书提供一种治疗与需要降低低密度脂蛋白胆固醇(high densitylipoprotein(LDL)-cholesterol)水平相关的疾病或障碍的方法，其包括对有需要的哺乳动物(特别是人)施用有效量的桦褐孔菌醇或其前体药物的化合物。
口服施用的固体制剂可以通过在所述豆类提取物中混合至少一种赋形剂例如，淀粉、碳酸钙、蔗糖或乳糖、明胶等来制备。此外，除了简单的赋形剂以外，还可以使用硬脂酸镁和滑石粉等润滑剂。
口服液体制剂包括悬浮液、口服溶液剂、乳剂、糖浆剂等，而除了作为常用单纯稀释剂的水和矿物油之外，还可以包括各种赋形剂，例如，润湿剂、甜味剂、芳香剂、保存剂等。
肠胃外施用制剂包括灭菌水溶液、水不溶性制剂、悬浮剂、乳剂、冻干制剂和栓剂。作为水不溶性制剂和悬浮剂，可以使用丙二醇、聚乙二醇、橄榄油等植物油和油酸乙酯等可注射酯等。作为栓剂的基质，可以使用半合成脂肪酸酯(witepsol)、聚乙二醇、吐温(tween)20、可可脂、月桂脂、甘油明胶等。
根据本发明一个方面的药物组合物的优选剂量可以根据患者的状况、体重、疾病严重程度、药物类型、施用途径和施用期而变化，但可以由本领域技术人员适当地选择。然而，为了获得理想的效果，可以每天以0.0001至2000mg/kg的剂量，优选0.001至2000mg/kg的剂量施用。可以每天施用一次，也可以分成数次施用。然而，本发明的范围不受所述剂量的限制。
根据本发明一个方面的药物组合物可以通过各种途径施用于哺乳动物，例如，大鼠、小鼠、家畜和人等。施用的所有方式可以根据例如，口服、直肠或静脉、肌肉、皮下、子宫内硬膜或脑室内(intracerebroventricular)注射进行。
本发明的另一个方面提供一种用于预防或改善肝X受体(Liver-X rece ptors，LXRs)介导的皮肤状况的化妆品组合物，其包括桦褐孔菌醇(Inotodi ol)、其前体药物或其药学上可接受的盐作为活性成分。
肝X受体介导的皮肤状态如上所述。
所述化妆品组合物可以具有例如，柔软化妆水、营养化妆水、按摩霜、营养霜、精华、面膜、凝胶、浓缩精华或皮肤粘附型的化妆品剂型。
除了作为活性成分的所述组合物之外，所述化妆品组合物还可以包括常规用于化妆品组合物的成分，例如，稳定剂、增溶剂、维生素、色素和调味剂等常规辅助剂和载体。
本发明的另一个方面提供一种用于预防或改善肝X受体介导的疾病的保健品，其包括桦褐孔菌醇(Inotodiol)、其前体药物或其药学上可接受的盐作为活性成分。
根据本发明一个方面的保健品，当把所述化合物用作保健品的添加剂时，其可以直接添加或与其他食品或食品成分一起使用，并且可以根据常规方法适当地使用。活性成分的混合量可以根据预防、保健或治疗等各类使用目的适当地确定。
保健品的剂型可以是任何剂型，不仅可以是散剂、颗粒剂、丸剂、片剂或胶囊剂的形式，也可以是一般食品或饮料剂型。
所述食品的种类没有特别限制，可以添加所述物质的食品的例子可以是肉类、香肠、面包、巧克力、糖果类、点心类、饼干类、比萨、方便面、其他面类、口香糖类、包括冰淇淋类的乳制品、各种浓汤、饮料、茶、补液、酒精饮料和维生素复合物等，可以包括所有常规意义上的食品。
通常在制备食品或饮料时，基于100重量份的原料，所述化合物的添加量可以是小于或等于15重量份，优选为小于或等于10重量份。然而，当以保健和卫生或以健康管理为目的长期摄取时，所述量可以小于或等于所述范围，并且由于使用了天然产物的分馏物，所以在安全性方面没有问题，因此，也可以使用大于或等于所述范围的量。
在根据本发明一个方面的保健品中的饮料可以与常规饮料同样地包括各种调味剂或天然碳水化合物等作为附加成分。所述天然碳水化合物可以是葡萄糖、果糖等单糖，麦芽糖、蔗糖等双糖，糊精、环糊精等多糖，以及木糖醇、山梨糖醇和赤藓糖醇等糖醇。作为甜味剂，可以使用索马甜、甜菊糖提取物等天然甜味剂，或使用糖精、阿斯巴甜等合成甜味剂等。基于每100mL的本发明的饮料，所述天然碳水化合物的比例可以是约0.01至0.04g，优选为约0.02至0.03g。
除了上述内容之外，根据本发明一个方面的保健品可以包括各种营养素、维生素、电解质、调味剂、着色剂、果胶酸及其盐、海藻酸及其盐、有机酸、保护性胶体增稠剂、酸度(pH)调节剂、稳定剂、防腐剂、甘油、酒精、碳酸饮料中使用的碳酸化剂。此外，本发明的用于改善睡眠的组合物可以包括用于制造天然果汁、果汁饮料和蔬菜饮料的果肉。这些成分可以单独或混合使用。这些添加剂的比例不受限制，但通常基于100重量份的本发明的保健品，在0.01至0.1重量份的范围进行选择。
发明效果
根据本发明一个方面的桦褐孔菌醇及其前体药物对肝X受体β(LXRβ)具有特异性激动剂活性，因此，与其他肝X受体(LXRs)激动剂相比不仅具有显著的稳定性，而且具有可以有效用于治疗肝X受体(LXRs)相关疾病的效果，例如，脑神经退行性疾病、自身免疫性疾病、非酒精性脂肪性肝炎(NASH)、非酒精性脂肪性肝病(NAFLD)等。
附图说明
图1是显示根据一个具体实施例的桦褐孔菌醇在肝脏样本中对肝X受体β(LXR-β)是特异性激动剂的图表。
图2是显示根据一个具体实施例的桦褐孔菌醇在脾脏样本中对肝X受体β(LXR-β)是特异性激动剂的图表。
图3是显示根据一个具体实施例的桦褐孔菌醇在腹膜腔细胞样本中对肝X受体β(LXR-β)是特异性激动剂的图表。
图4是显示根据一个具体实施例的桦褐孔菌醇在肺脏样本中对肝X受体β(LXR-β)是特异性激动剂的图表。
图5是显示根据一个具体实施例的桦褐孔菌醇在胸腺样本中对肝X受体β(LXR-β)是特异性激动剂的图表。
图6是证实根据一个具体实施例的桦褐孔菌醇增加与抑制脑神经退行性疾病相关的基因表达的图表。
图6a是证实根据一个具体实施例的桦褐孔菌醇增加与抑制脑神经退行性疾病相关的基因，即ATP结合盒转运蛋白A1(ABCA1)表达的图表，图6b是证实根据一个具体实施例的桦褐孔菌醇增加与抑制脑神经退行性疾病相关的基因，即载脂蛋白E(APOE)的表达的图表。
图7是显示根据一个具体实施例的桦褐孔菌醇对类风湿性关节炎有效的类风湿性关节炎评分(Rheumatoid arthritic score)的图表。
图8是显示根据一个具体实施例的桦褐孔菌醇抑制肿瘤坏死因子-α(TNF-α)表达的图表。
具体实施方式
在下文中，呈现优选的实施例以帮助理解本发明。然而，提供以下实施例是为了更容易理解本发明，本发明的内容不受以下实施例的限制。
实施例1.分析桦褐孔菌醇在体内(In vivo)对肝X受体(LXRs)相关因子产生的影响
分析了桦褐孔菌醇对作为与肝X受体(LXRs)相关的标志物的ATP结合盒转运蛋白A1(Abca1)、固醇调节元件结合转录因子1c(Srebf1_1C)、水通道蛋白1(AQP1)和载脂蛋白E1(ApoE1)的影响。
首先，制备桦褐孔菌醇乳剂，以用于4mg/kg剂量的施用。具体而言，通过混合桦褐孔菌醇与10％的橄榄油(olive oil)(莫尼尼，经典特级初榨橄榄油(Monini,Classicoextra virgin olive oil))、0.5％的吐温80(tween 80)和无菌水来制备乳剂。此后，每天将所述制备的乳剂以0.15mL的量持续5天施用于BALB/cAnNTacSam(Sam Taco Bio KoreaCo.，Ltd.)。施用5天后，对小鼠执行安乐死后，分离脾脏、肺脏、肝脏和腹膜腔细胞样本。
接下来，为了对所述分离的样本进行实时荧光定量PCR(qPCR)，使用BeadTMTotalRNA Prep Kit(BioFACTTM)样本分离总RNA。然后，使用了ATP结合盒转运蛋白A1(Abca1)、固醇调节元件结合转录因子1c(Srebf1_1C)、水通道蛋白1(AQP1)和载脂蛋白E1(ApoE1)的引物，并且用于实时荧光定量PCR(qPCR)的反应试剂是2X Real-Time PCR Master Mix(BioFACTTM)，而为进行实时荧光定量PCR(qPCR)所用的仪器是AriaMx Real-time PCR。实时荧光定量PCR(qPCR)的条件是95℃(15分钟)、95℃(20秒)-55℃(30秒)-72℃(0.5-1min/kb)进行50个循环(cycle)、熔解曲线(melting curve)为95℃(30秒)-65℃(30秒)-95℃(30秒)下进行1个循环(cycle)，然后测量mRNA的相对表达量。作为对照组，使用未处理的对照组，其结果如图1至图4所示。
图1是显示根据一个具体实施例的桦褐孔菌醇在肝脏样本中对肝X受体β(LXR-β)是特异性激动剂的图表。
图2是显示根据一个具体实施例的桦褐孔菌醇在脾脏样本中对肝X受体β(LXR-β)是特异性激动剂的图表。
图3是显示根据一个具体实施例的桦褐孔菌醇在腹膜腔细胞样本中对肝X受体β(LXR-β)是特异性激动剂的图表。
图4是显示根据一个具体实施例的桦褐孔菌醇在肺脏样本中对肝X受体β(LXR-β)是特异性激动剂的图表。
图5是显示根据一个具体实施例的桦褐孔菌醇在胸腺样本中对肝X受体β(LXR-β)是特异性激动剂的图表。
如图1至图5所示，可以发现根据一个具体实施例的桦褐孔菌醇在各个样本中增加ATP结合盒转运蛋白A1(Abca1)、固醇调节元件结合转录因子1c(Srebf1_1C)、水通道蛋白1(AQP1)和载脂蛋白E1(ApoE1)的表达。
这些结果表明，桦褐孔菌醇通过与肝X受体(LXRs)结合激活了作为相关基因的ATP结合盒转运蛋白A1(Abca1)、固醇调节元件结合转录因子1c(Srebf1_1C)、水通道蛋白1(AQP1)和载脂蛋白E1(ApoE1)的转录调节功能。
此外，已知在肝脏中肝X受体α(LXR-α)通常以高水平表达，而肝X受体β(LXR-β)以低水平表达。因此，在肝脏样本中，所述标志物中受肝X受体α(LXR-α)特异性调节的固醇调节元件结合转录因子1(Srebf1)的表达未明显增加，而受肝X受体β(LXR-β)调控的水通道蛋白1(AQP1)的表达则显示出明显的增加，因此可以发现桦褐孔菌醇不能很好地与肝X受体α(LXR-α)结合，而是通过更加特异性地与肝X受体β(LXR-β)以激动剂发挥作用。
因此，这些结果不仅表明肝X受体(LXRs)可以有效用于治疗肝X受体(LXRs)介导的疾病，例如，动脉粥样硬化、阿尔茨海默病、非酒精性脂肪性肝炎(NASH)、非酒精性脂肪性肝病(NAFLD)、代谢性疾病、皮炎等，而且还表明因为对肝X受体β(LXR-β)具有特异性，所以与其他肝X受体(LXRs)激动剂相比其更加能够确保安全。
实施例2.分析桦褐孔菌醇在体内(In vivo)的安全性
与所述实施例1相同，对小鼠的肝毒性进行了评估，以证实桦褐孔菌醇是一种确保安全性的肝X受体β(LXR-β)激动剂。当桦褐孔菌醇成为肝X受体α(LXR-α)的激动剂时，其会通过在肝脏中过度表达固醇调节元件结合转录因子1(Srebf1)来诱发肝脂肪变性。通过为期2周的小鼠毒性实验评估了桦褐孔菌醇的肝X受体(LXRs)选择性和安全性。
具体而言，使用雄性和雌性ICR小鼠每天1次以0.0mg/kg(第1组(group 1))、5.0mg/kg(第2组(group 2))和20mg/kg(第3组(group 3))的剂量持续2周口服施用所述桦褐孔菌醇乳剂。作为参考，治疗哮喘和食物过敏等的桦褐孔菌醇的适当剂量浓度预计是4.5至5.0mg/kg。作为对照组，施用100％的橄榄油。实验中使用的所有对象均未发现健康异常迹象，对所有存活动物施用15天后，使用异氟烷麻醉后将其安乐死，然后分离肝脏组织以分析总脂肪含量，其结果如下表1所示。如表1中总结的，无论是在5mg/kg剂量，还是在20mg/kg剂量的情况，雌性和雄性小鼠的肝脏总脂肪含量均未显示显著变化。
【表1】
实施例3.分析体内(In vivo)血液和脑组织中的桦褐孔菌醇的浓度
分析了当对小鼠施用桦褐孔菌醇时，在小鼠的血液和脑组织中检测到的桦褐孔菌醇的浓度。
具体而言，接收7周龄的Balb/c小鼠并驯化1周，然后每组分配4只小鼠以进行实验。分成4组未施用桦褐孔菌醇的对照组和4组施用桦褐孔菌醇的组。施用桦褐孔菌醇的组以4.5mg/kg的剂量持续10天口服施用桦褐孔菌醇。第11天，处死对照组和施用桦褐孔菌醇的组的小鼠，以准备血液和脑组织样本。
首先，为了分析血液中桦褐孔菌醇的浓度，将20μL的血清转移到1.5mL的微量离心(Eppendorf)管中后，在乙醇中提取2次桦褐孔菌醇。在每个提取步骤中，将200μL的乙醇与血清混合，并且将混合物超声处理10分钟后，以14000xg离心15分钟。
为了分析脑组织中的桦褐孔菌醇的浓度将整个大脑称重，并且与10倍(v/w)的100％乙醇混合后，将混合物超声处理后离心。
离心后，用0.5mL的60％甲醇重构每个渗余物，以使用C18柱(Sep-Pak C18 3cc真空滤芯(Sep-Pak C18 3cc Vac Cartridge)，200mg吸附剂，沃特世(Waters))进行固相萃取。将样本加载到小柱上并使用甲醇(6mL)激活后，使用60％甲醇(6mL)进行调节。然后，使用6mL的60％甲醇洗涤小柱。然后，在玻璃管中使用100％甲醇(3mL)洗脱小柱以收集桦褐孔菌醇。蒸发样品后，将渗余物溶解在甲醇中并进行了液相色谱-质谱联用(LC/MS)分析。
其结果如表2所示，在对照组中的脑组织和血液中未检测出桦褐孔菌醇，而在施用桦褐孔菌醇的组中的脑组织检测出平均为151.7±21.3ng/g的桦褐孔菌醇，在血液中检测出平均为12.1±1.3ng/g的桦褐孔菌醇，因此已证实在大脑中检测到的桦褐孔菌醇为血液中桦褐孔菌醇的约12倍。
这些结果表明桦褐孔菌醇可以被有效地输送到动物的大脑。
【表2】
实施例4.分析体内(In vivo)脑组织中与脑神经退行性疾病相关的基因的表达
分析了当对小鼠施用桦褐孔菌醇时，在脑组织中作为与脑神经退行性疾病相关的基因的ATP结合盒转运蛋白A1(ABCA1)和载脂蛋白E(APOE)的表达。
具体而言，与所述实施例3相同，准备对照组和施用桦褐孔菌醇的组的小鼠后，先对50mg的脑组织样本进行定量，然后使用研钵粉碎了细胞，以提取总RNA(total RNA)。将1mL的Trizol分注到粉碎的样本中并通过涡旋混合。然后，分注0.2mL的三氯甲烷后，在常温下反应3分钟。在12000rpm、4℃下离心15分钟后，仅将透明上清液转移至新管中，然后分注0.5mL的异丙醇(Isopropyl alcohol)后，在常温下反应10分钟。在12000rpm、4℃下离心10分钟后完全去除上清液，然后使用1mL的75％乙醇(Ethanol)去除杂质。在7500rpm、4℃下离心5分钟后，加入75％乙醇(Ethanol)后离心，然后尽可能去除上清液后，在55℃加热块(Heat block)上干燥了约5分钟。使用DEPC水(DEPC water)溶解样本后，使用Nanodrop将总RNA(Total RNA)定量至1000ng/uL，然后使用primeScript RT Master Mix(Takara Korea)进行cDNA合成。使用Smartgene Sybr Green Q-PCR master mix(Samjung Bioscience)和对载脂蛋白E(APOE)基因及ATP结合盒转运蛋白A1(ABC A1)基因具有特异性的引物进行实时荧光定量PCR(real-time PCR)。
其结果如图6所示，与未施用桦褐孔菌醇的对照组(Naive)相比，施用桦褐孔菌醇的组(Ino(10mpk))在脑组织中ATP结合盒转运蛋白A1(ABCA1)和载脂蛋白E(APOE)基因高表达。已知ATP结合盒转运蛋白A1(ABCA1)激活载脂蛋白E(APOE)并抑制大脑中的炎症，并且载脂蛋白E(APOE)的激活消除β-淀粉样蛋白。
图6是证实根据一个具体实施例的桦褐孔菌醇增加与抑制脑神经退行性疾病相关的基因表达的图表。
图6A是证实根据一个具体实施例的桦褐孔菌醇增加作为与抑制脑神经退行性疾病相关的基因的ATP结合盒转运蛋白A1(ABCA1)表达的图表，图6B是证实根据一个具体实施例的桦褐孔菌醇增加作为与抑制脑神经退行性疾病相关的基因的载脂蛋白E(APOE)的表达的图表。
因此，这些结果表明，桦褐孔菌醇促进β-淀粉样蛋白的排出和分解，具有降低小胶质细胞(Microglial cell)炎症反应的效果，并且这也表明桦褐孔菌醇可以有效用于治疗脑神经退行性疾病。
实施例5.证实桦褐孔菌醇对类风湿性关节炎和银屑病的体内(In vivo)治疗效果
为了证实给小鼠施用桦褐孔菌醇是否具有治疗类风湿性关节炎的效果，将牛II型胶原蛋白(bovine type II collagen)施用于雄性DBA/1J小鼠以诱发关节炎后，口服施用桦褐孔菌醇。
具体而言，经过6天的驯化期后，在牛II型胶原蛋白(Bovine type II collagen)(2mg/mL溶于0.05mol/L的乙酸(acetic acid)；Chondrex,Inc.,美国(USA))中缓慢混合等量的完全弗氏佐剂(complete Freund’s adjuvant)(Chondrex，Inc.，美国(USA))的同时，使用均质器(homogenizer)制备乳剂后，使用一次性注射器以0.05mL/头(head)施用于小鼠尾部皮下的方法进行二次免疫(immunization)以诱发关节炎。
对于未诱发关节炎的动物，选取健康无异常且接近平均体重的6只作为正常对照组，并且对于诱发关节炎的动物，选取健康无异常且接近平均体重的18只后，每组分配6只以使每组的平均体重相等。将诱发关节炎的动物分成未施用桦褐孔菌醇的组、施用4mg/kg的桦褐孔菌醇的组和施用10mg/kg的桦褐孔菌醇的组。使用带有探头的一次性注射器，从施用起始日起，以1次/天，持续4周，共计28次向胃里强制施用。
对于关节炎症状的肉眼观察从施用起始日起，以2次/周进行4周。肉眼观察每只动物的每条腿的膝盖、脚踝和脚背，并且根据下表3中的肉眼性关节炎指数(macroscopicarthritic index)评价标准记录关节炎指数。通过对每只动物的每条腿的关节炎指数求总和，计算出了每只个体的肉眼性关节炎评分(macroscopic arthritic score，最高评分＝16)。
【表3】
其结果如图7所示，已证实与未施用桦褐孔菌醇的关节炎动物相比，施用桦褐孔菌醇的关节炎动物的关节炎评分更低。
图7是显示根据一个具体实施例的桦褐孔菌醇对类风湿性关节炎有效的类风湿性关节炎评分(Rheumatoid arthritic score)的图表。
接下来，证实了作为激活炎症因子的肿瘤坏死因子-α(TNF-α)的表达。
具体而言，将能够与小鼠肿瘤坏死因子-α(TNF-α)特异性结合的一抗(Biolegend)在包被缓冲液(coating buffer)中稀释，并且以0.5至8ug/mL的浓度，在板中以100ul分注后，在4℃下保存18小时。然后，去除包被缓冲液(coating buffer)后，以每次200uL的洗涤缓冲液(washing buffer，0.05％Tween20/PBS)洗涤(washing)3次。为了阻止非特异性结合，将200uL的封闭液(blocking solution，1％BSA/PBS)在常温下反应1小时。使用洗涤缓冲液(washing buffer)洗涤(washing)3次。使用封闭液(blocking solution)稀释标准参考物质(Biolgend)和样本后，分别分注100uL后，在常温下反应2至4小时。使用洗涤缓冲液(washing buffer)洗涤(washing)3次。使用封闭液(blocking solution)将二抗(生物素标记检测抗体(biotin-labeled detection antibody)，biolegend)稀释至0.25至2ug/mL后分注100ul，然后在常温下反应1小时。使用洗涤缓冲液(washing buffer)洗涤(washing)3次。使用封闭液(blocking solution)将亲和素-辣根过氧化物酶(Avidin-Horseradishperoxidase，Biolegend)稀释至1/1000倍后分注100uL，然后在常温下反应30分钟。使用洗涤缓冲液(washing buffer)洗涤(washing)5次。将TMB(Biolegend)分注100uL后，反应4至30分钟，并且当颜色发生变化时，将2N H2SO4分注100uL以终止反应。使用EPOCH酶标仪(EPOCH microplate reader，Biotek)在450nm处确认酶标板(ELISA plate)。
其结果如图8所示，已证实在施用桦褐孔菌醇的关节炎动物中肿瘤坏死因子-α(TNF-α)的表达更低。
图8是显示根据一个具体实施例的桦褐孔菌醇抑制肿瘤坏死因子-α(TNF-α)表达的图表。
如上所述结果表明，桦褐孔菌醇不仅可以有效地用于治疗类风湿性关节炎，而且还可以有效地用于治疗银屑病。
以上所述对本发明的描述是用于示例，本领域的技术人员可以理解在不改变本发明的技术精神或必要特征的情况下，可以容易地将其修改为其他具体形式。因此，以上所述实施例应理解为在所有方面都是示例性的而不是限制性的。
Claims (13)
1.一种肝X受体激动剂，其包括桦褐孔菌醇、其前体药物或其药学上可接受的盐作为活性成分。
2.一种用于预防或治疗肝X受体介导的疾病的药物组合物，其包括桦褐孔菌醇、其前体药物或其药学上可接受的盐作为活性成分。
3.根据权利要求2所述的药物组合物，所述前体药物是如下式1所示的桦褐孔菌醇化合物的羟基与脂肪酸、葡糖醛酸、烷基琥珀酸酐或酚酸的羧基通过酯缩合反应形成的桦褐孔菌醇酯衍生物化合物：
[式1]
4.根据权利要求3所述的药物组合物，所述桦褐孔菌醇酯衍生物化合物由下式2表示：
[式2]
所述式中，R1和R2各自独立地为OH或-OC(O)-R3，并且R3是具有1个至30个碳原子数的直链或支链烷基、烯基或炔基，
并且R1和R2中至少有一个是-OC(O)-R3。
5.根据权利要求4所述的药物组合物，所述R3是具有CH3(CH2)a-或CH3(CH2)b(CH＝CH[CH2])c(CH2)d-的未取代的直链烷基或烯基，并且a是8至24的整数，b是1至5的整数，c是1至6的整数，d是3至7的整数。
6.根据权利要求2所述的药物组合物，所述桦褐孔菌醇或其前体药物是向上调节肝X受体的表达或活性的桦褐孔菌醇激动剂。
7.根据权利要求2所述的药物组合物，所述肝X受体介导的疾病是选自由脑神经退行性疾病、自身免疫性疾病、动脉粥样硬化、血脂异常症、脑卒中、高脂血症、高胆固醇血症、高脂蛋白血症、高三酰甘油血症、脂质营养不良、肝脂肪变性、非酒精性脂肪性肝炎、非酒精性脂肪性肝病、高血糖症、胰岛素抵抗、肥胖、胆结石、代谢综合征、X综合征、外周闭塞性疾病、尿蛋白、肾小球病、高血压肾病、IGA肾病、局灶节段性肾小球硬化症、特应性、痤疮、接触性皮炎、高磷血症、高磷血症相关的心血管并发症、癌症和骨质疏松症组成的组中的任何一种。
8.根据权利要求7所述的药物组合物，所述脑神经退行性疾病是选自由痴呆症、阿尔茨海默病、帕金森病、亨廷顿舞蹈症、轻度认知障碍、脑淀粉样血管病、唐氏综合症、淀粉样变性脑卒中、系统性淀粉样变性、荷兰型淀粉样变性、尼曼-皮克病、老年性痴呆症、肌萎缩侧索硬化、脊髓小脑萎缩症、图雷特综合征、弗里德赖希共济失调、马查多-约瑟夫病、路易体痴呆、肌张力障碍、进行性核上性麻痹和额颞痴呆组成的组。
9.根据权利要求7所述的药物组合物，所述自身免疫性疾病是选自由类风湿性关节炎、银屑病、皮炎、多发性硬化和糖尿病组成的组。
10.一种用于预防或改善肝X受体介导的疾病的保健品，其包括桦褐孔菌醇、其前体药物或其药学上可接受的盐作为活性成分。
11.一种用于预防或改善肝X受体介导的皮肤状况的化妆品组合物，其包括桦褐孔菌醇、其前体药物或其药学上可接受的盐作为活性成分。
12.一种用于预防或治疗肝X受体介导的疾病的方法，其包括将桦褐孔菌醇、其前体药物或其药学上可接受的盐施用于需要其的个体。
13.一种桦褐孔菌醇、其前体药物或其药学上可接受的盐用于制备用于预防或治疗肝X受体介导的疾病的组合物的用途。
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