TWI751716B - 一種具有甲狀腺激素受體激動劑特性的肝標靶化合物及其藥物組合物 - Google Patents
一種具有甲狀腺激素受體激動劑特性的肝標靶化合物及其藥物組合物 Download PDFInfo
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- TWI751716B TWI751716B TW109132625A TW109132625A TWI751716B TW I751716 B TWI751716 B TW I751716B TW 109132625 A TW109132625 A TW 109132625A TW 109132625 A TW109132625 A TW 109132625A TW I751716 B TWI751716 B TW I751716B
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- liver
- thyroid hormone
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- receptor agonist
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Abstract
本發明屬於生物醫藥領域,具體涉及標靶藥物領域,更具體地說,本發明涉及一種具有甲狀腺激素受體激動劑特性的肝標靶化合物及其藥物組合物,該化合物為式(1)所示的化合物。該化合物可用於治療和/預防由甲狀腺激素調節失調引起的疾病,也可以有效降低血漿及肝臟細胞中的脂質。
Description
本發明屬於生物醫藥領域,具體涉及標靶藥物領域,更具體地說,本發明涉及一種具有甲狀腺激素受體激動劑特性的肝標靶化合物及其藥物組合物。
作為一種慢性肝病,非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)的特徵是肝細胞內脂質的過度積累,主要是三酸甘油酯(triglycerides,TGs)的過度積累。NAFLD的病變過程包括一系列肝臟的病理變化,從肝細胞內簡單的三酸甘油酯積累(肝脂肪變性)到炎症性和肝細胞球囊性損傷,發展成非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH),最終導致肝纖維化和肝硬化。脂肪變性向脂肪性肝炎轉變的確切機制尚不清楚。有二次打擊的假說:第一次打擊涉及肝細胞中TGs的積累,導致代謝功能障礙的惡性循環。一旦肝脂肪變性的存在被確定,進展為脂肪性肝炎涉及氧化應激起關鍵作用的第二次打擊。目前NAFLD/NASH是一種在世界範圍內越來越普遍的慢性肝病,並且趨於年輕化。公開資料顯示,NAFLD全球發病率為15%至30%,其中10%至20%會發展成為NASH。據不完全統計,2016年中國約有2.4億NAFLD人群,到2030年,預計NAFLD人群將增加到約3.1億,其中患有肝硬化的患者將達到約230萬。在美國,《自然》雜誌2017年的一篇文章指出,NASH已經成為繼慢性C型肝炎之後肝移植的第二大原因,並預計在2020年實現超越,登頂美國肝移植的首要原因。之所以造成如此局面,主要原因在於,目前NASH尚無公認的藥理學治療方法及人們對這類疾病的不重視。目前,
NASH已知的主要發病因素包括肥胖、第二型糖尿病、高血脂及高血壓等代謝症候群。全球範圍內尚未出現針對該適應症的治療藥物獲批上市。目前治療干預的方法主要是基於生活方式的改變,包括飲食和運動,但效果並不明顯。
甲狀腺激素T4(thyroxine)和T3(triiodothyronine)具有多種作用,是調節糖、脂代謝和體重的有效物質。特別是,他們發揮了重要肝脂質恆定作用。他們發揮生理效應通過綁定到其特異的核受體,甲狀腺激素受體(thyroid hormone receptor,TR)TR-α和TR-β。通過與廣泛分佈在全身的特定激素受體TR-α和TR-β相互作用而產生影響。TR-β主要集中在肝臟表達,對脂質代謝有重要影響,包括降低低密度脂蛋白(low-density lipoprotein,LDL)膽固醇和三酸甘油酯,減少全身肥胖和體重(Pramfalk C等,Biochim Biophys Acta 1812:929-937),並且可以通過提高肝臟的脂質代謝率來降低脂質含量。Perra A等的一項研究結果表明,T3可以抑制肝細胞脂肪變性,並修復已脂肪變性的肝細胞(Perra A等,FASEB J 22:2981-2989)。但是,過量的甲狀腺激素容易引起副作用,副作用包括促甲狀腺激素(thyroid stimulation prepituitary hormone,TSH)、心臟以及骨骼和肌肉的不良反應(Braverman LE等,editors.Lippincott:The Thyroid 2000:515-517)及肝功能的損傷,從而導致ALT(alanine transaminase)、AST(aspartate transaminase)及GGT(gamma-glutamyl transferase)等肝酶的升高。促甲狀腺激素(TSH)是由腺垂體(adenohypophysis)分泌的激素,腺垂體分泌促甲狀腺激素,一方面受下視丘分泌的促甲狀腺激素釋放激素(thyrotropic hormone-releasing hormone,TRH)的促進性影響,另一方面又受到甲狀腺激素回饋性的抑制性影響,二者互相拮抗,它們組成下視丘-腺垂體-甲狀腺軸。
促甲狀腺激素TSH主要負責調節甲狀腺細胞的增殖、甲狀腺血液供應以及甲狀腺激素的合成和分泌,在維持正常甲狀腺功能中起最重要的調節作用。垂體本身的疾病可以直接影響到TSH的合成和釋放。當甲狀腺本身原
因導致甲狀腺激素合成和分泌異常時,也可影響到垂體TSH的分泌和血清TSH濃度。同樣,下視丘疾病影響到TRH分泌時也會影響垂體的TSH的分泌和血清TSH濃度。
促甲狀腺激素TSH的主要作用就是控制甲狀腺。它能促進甲狀腺激素的合成,還能促進已生成的甲狀腺激素釋放入血。對甲狀腺本身的生長和新陳代謝也起著重要作用,外源性的甲狀腺激素進入體內,可使促甲狀腺激素出現類似甲狀腺激素回饋性的抑制性影響,從而影響促甲狀腺激素的正常分泌,容易引發甲狀腺亢進現象,出現心率加快或TSH降低的現象。臨床中,一個藥物如果使心率加快15%和使促甲狀腺激素TSH降低30%,就說明了這個藥物對心臟和甲狀腺有副作用。有文獻研究證明,T3引發心率加快15%的ED15以及抑制促甲狀腺激素TSH 30%的ED30與降低高膽固醇TC的ED50(median effective dose)的比值分別為1.5和0.4(GARY J等,Endocrinology 145(4):1656-1661),所以外源性甲狀腺激素雖然顯現出良好降脂和抑制肝細胞脂肪變性的效果,但其並不適合作為臨床調節脂質代謝或NASH治療的藥物。由於甲狀腺激素的這些不利影響,限制了其在脂質代謝及NASH治療方面的進一步應用。如果能夠消除或減少甲狀腺激素對甲狀腺軸及心臟和其他臟器的副作用,就可以獲得能夠預估的治療效果。
甲狀腺激素β受體激動劑,是一類基於甲狀腺激素T3結構改造的新化合物或他們的前驅化合物。甲狀腺激素是通過與各種組織中的甲狀腺激素受體TR-α和TR-β的結合,對有機體的分化發育和代謝平衡進行調節。甲狀腺激素β受體激動劑可以選擇性作用於TR-β1的亞型TR-β1,對TR-β1的親和力和選擇性遠大其對TR-α的作用。TR-β1存在於大多數組織中,尤其是肝臟,在心臟中分佈較少,其介導了甲狀腺素在肝臟和脂肪組織的作用。基於甲狀腺激素T3結構改造的新化合物或他們的前驅化合物保留了甲狀腺激素上述作用,且呈現
出較少的TR-α方面及對肝功能的副作用,目前是治療非酒精性脂肪性肝病(NAFLD)新藥的重要開發領域。
為了減少用於治療NAFLD或NASH的藥物的副作用,在生物醫藥領域迫切需要開發出一種新藥,該新藥既能夠保持甲狀腺素在肝內的脂質代謝作用,又不會到其他組織導致相應的副作用。
本發明的一個目的是提供一種具有甲狀腺激素受體激動劑特性的肝標靶化合物。
本發明的另一個目的是提供一種製備具有甲狀腺激素受體激動劑特性的肝標靶化合物的方法。
本發明的又一個目的是提供一種具有甲狀腺激素受體激動劑特性的肝標靶化合物的用途。
本發明的再一個目的是提供一種包含具有甲狀腺激素受體激動劑特性的肝標靶化合物的藥物組合物。
其中,n為1至10的整數,較佳為1至3的整數;X為羰基;Y為NH或氧原子。
外源性甲狀腺激素進入體內,會進行全身分佈,從而引發對甲狀腺軸、心臟、肌肉、骨骼及肝功能的副作用。
N-乙醯半乳糖胺對肝臟中去唾液酸糖蛋白受體(asialoglycoprotein receptor,ASGPR,一種肝細胞特異性表達的受體)具有高親和力。可以使結構中含有半乳糖胺的化合物具有主動肝靶向性,可以使甲狀腺激素β受體激動劑在其自身具有高的TR-β1的親和力和選擇性的基礎上,還具有主動肝靶向,進一步減少其他組織的分佈,減少其副作用。
本發明提供的具有甲狀腺激素受體激動劑特性的肝標靶化合物中左側末端含有三個半乳糖胺結構,右側末端是一個T3類似結構,通過酯化或醯胺化連接,使整個化合物不僅具有肝靶向性和保持甲狀腺激素β受體激動劑的作用,還最大限度地減少了副作用的發生。
其中,n為1至10的整數,較佳為1至3的整數;X1為-COOH;Y1為胺基或羥基;X1和Y1也可以是其他使化合物A和化合物B之間形成酯或醯胺的基團。
本發明的又一方面提供了具有甲狀腺激素受體激動劑特性的肝標靶化合物在製備用於治療和/或預防由甲狀腺激素調節所引起之疾病的藥物中的用途,其中,所述疾病,包括代謝性疾病、肥胖、高血脂症、高膽固醇血症、糖尿病、非酒精性脂肪性肝病、非酒精性脂肪性肝炎、酒精性脂肪性肝病、酒精性脂肪性肝炎、動脈粥樣硬化、心血管疾病、甲狀腺功能減退、甲狀腺癌。
在本發明的較佳實施方案中,所述疾病為非酒精性脂肪性肝病或非酒精性脂肪性肝炎。
本發明的再一方面提供了一種用於治療和/或預防由甲狀腺激素調節所引起之疾病的藥物組合物,該藥物組合物包含治療有效量的上述具有甲狀腺激素受體激動劑特性的肝標靶化合物以及選擇性存在(optional)的藥學上可接受之賦形劑,其中,所述藥學上可接受之賦形劑包括腸道吸收促進劑,其包括中鏈脂肪酸鈉鹽、膽酸鹽、環糊精及其衍生物、陽離子型聚合物、陰離子型聚合物及巰基化聚合物。
在本發明的一個實施方案中,所述中鏈脂肪酸鈉鹽為癸酸鈉,較佳地,所述具有甲狀腺激素受體激動劑特性的肝標靶化合物與癸酸鈉的重量比為1:0.2至1:0.75。
在本發明的較佳實施方案中,所述藥物組合物的劑型為注射劑,或者為速釋或緩釋的口服製劑。
本發明提供的化合物或藥物組合物可用於哺乳動物臨床使用,包括人和動物,可以通過口、鼻、皮膚、肺或者胃腸道等的途徑給藥。最佳的
給藥途徑為口服。最佳的日劑量為0.08毫克/公斤體重(mg/kg體重)至10mg/kg體重,一次性服用,或0.08mg/kg體重至5mg/kg體重,分次服用。不管採用何種服用方法,個人的最佳劑量應依據具體的治療方案而定。通常情況下是從小劑量開始,逐漸增加劑量一直到找到最適合的劑量。
綜上所述,本發明提供的具有甲狀腺激素受體激動劑特性的肝標靶化合物的優點有二:1)利用N-乙醯半乳糖胺對肝臟細胞表面的去唾液酸糖蛋白受體的高親和力增強對肝臟的靶向性,減少其在其他組織中的分佈;2)利用T3結構類似物具有對TR-β的高親和力作用;進而降低不必要的副作用。二者組合成一個完整的化合物,使之能夠特異性進入到肝臟細胞發揮甲狀腺激素受體激動劑的作用,調節脂質代謝、逆轉肝脂肪變和炎症,減緩肝纖維化。
與現有技術相比,本發明提供的具有甲狀腺激素受體激動劑特性的肝標靶化合物的技術效果如下:目前國內外臨床還沒有一種正式用於治療NAFLD或NASH的藥物,本發明提供的具有甲狀腺激素受體激動劑特性的肝標靶化合物具有甲狀腺激素β受體的特性,還具有主動肝靶向性,克服了外源性甲狀腺激素及早期甲狀腺激素β受體激動劑雖然對β1受體有高的選擇性,但其還是存在對甲狀腺軸、心臟、肌肉、骨骼和肝功能的副作用,是一種極具市場潛力的藥物。本發明提供的化合物GBL-0603能夠有效的降低db/db小鼠血清的膽固醇(CHO)、低密度脂蛋白(LDL)、三酸甘油酯(TG)(圖3、8);同時,化合物GBL-0603能夠降低db/db小鼠肝內的CHO和TG(圖4、9);病理組織檢測顯示肝內的脂肪病變隨著劑量的增加而得到改善(圖5);無論對db/db和正常小鼠都沒有顯現出對心臟、骨密度、骨的礦物質含量的影響(圖6、10、11、12);化合物GBL-0603能明顯減少db/db小鼠肝臟的重量。另外,與本發明人早期發明的化合物Kylo-0101相
比,新開發的化合物GBL-0603對肝臟功能的影響更為輕微(圖15、16);在各個劑量下GBL-0603甲狀腺素軸的各個指標沒有明顯變動(圖17)。
為了使本發明的目的、技術方案和有益效果更加清楚,本發明提供如下附圖說明:圖1為化合物B高解析度質譜圖;圖2為化合物GBL-0603高解析度質譜圖;圖3為實施例2中,GBL-0603降低db/db肥胖模型小鼠血清中的CHO、TG和LDLC效果圖;圖4為實施例2中,GBL-0603降低db/db肥胖模型小鼠肝臟組織細胞內的CHO和TG效果圖;圖5為實施例2中,GBL-0603 HE染色肝臟切片病理組織學改變示例圖;圖6為實施例2中,GBL-0603對db/db肥胖模型小鼠心臟重量的影響圖;圖7為實施例2中,GBL-0603對db/db肥胖模型小鼠肝臟重量的影響圖;圖8為實施例3中,GBL-0603對db/db肥胖模型小鼠血清中的CHO、TG和LDLC影響圖;圖9為實施例3中,GBL-0603對db/db肥胖模型小鼠肝臟中的CHO和TG影響圖;圖10為實施例4中,GBL-0603對正常小鼠骨密度影響圖;圖11為實施例4中,GBL-0603對正常小鼠骨礦物質含量影響圖;
圖12為實施例4中,GBL-0603對正常小鼠心臟重量影響圖;圖13為實施例4中,GBL-0603對正常小鼠肝臟重量影響圖;圖14為實施例4中,GBL-0603對正常小鼠體重影響圖;圖15為實施例4中,GBL-0603對正常小鼠肝功能影響圖;圖16為實施例4中,Kylo-0101對正常小鼠肝功能影響圖;圖17為實施例4中,GBL-0603對正常小鼠血清中T3、fT3、T4、fT4、TSH的影響圖。
以下實施例說明了本發明公開的一些實施方案,但並不局限於這些。此外,在提供具體實施方案時,本發明人預期了那些具體實施方案的應用。例如具有具體同類或類似化學結構的化合物,用於不同的肝源性疾病的治療。
說明:
DMF的中文名稱為N,N-二甲基甲醯胺(N,N-dimethylformamide);HOBt的中文名稱為1-羥基苯並三唑(1-hydroxybenzotriazole);DIPEA的中文名稱為N,N-二異丙基乙胺(N,N-diisopropylethylamine);Pd/C的中文名稱為鈀活性炭(palladium on carbon);TBTU的中文名稱為O-苯並三氮唑-N,N,N',N'-四甲基脲四氟硼酸(O-(benzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium tetrafluoroborate);DCM的中文名稱為二氯甲烷(dichloromethane);NBS的中文名稱為N-溴代丁二醯亞胺(N-bromosuccinimide);n-BuLi的中文名稱為正丁基鋰(n-butyllithium);
TIPSCl的中文名稱為三異丙基氯矽烷(chlorotriisopropylsilane);THF的中文名稱為四氫呋喃(tetrahydrofuran);MTBE的中文名稱為甲基叔丁基醚(methyl tert-butyl ether);TBAF的中文名稱為四丁基氟化銨(tetrabutylammonium fluoride)。
本發明中所涉及兩種物質的比,在沒有特別註明的情況下均指體積比;本發明中所涉及的含量,在沒有特別註明的情況下均指體積百分濃度。
實施例1:化合物GBL-0603的製備
1、化合物A的合成
1.1 化合物A-c1的合成
向反應瓶內依次加入DMF(8mL)、cbz-6-胺基己酸(24mg)、HOBt(21.6mg)、dlSANC-c12(84mg)和DIPEA(53.5mg),加料完畢,室溫攪拌反應過夜,TLC檢測,反應合格,停止反應,進行後處理,加水淬滅,靜止分相,水相用DCM萃取三次,20毫升/次(mL/次),合併有機相,用飽和氯化鈉水溶液洗滌、無水硫酸鈉乾燥、濃縮、通過管柱純化,得到白色固體72.8毫克(mg)。
1.2 化合物A的合成
向反應瓶內依次加入化合物A-c1(72.8mg)、甲醇15mL、Pd/C(3.4mg),進行真空/氫氣置換,置換完畢,通入H2,40℃攪拌反應1.0小時(h),TLC分析,反應合格,停止反應,過濾,除掉Pd/C,濾液進行濃縮,得到47mg的白色固體。
2、化合物B的合成
2.1 化合物B-c1的合成
稱量2-異丙基苯酚(30.3mg),溶於乙腈中(10mL),加入NBS(34.2mg),於35℃反應6h。反應液濃縮,再溶於石油醚(50mL),過濾除去不溶物,濾液分別用水(40mL)和吡啶(40mL)洗滌,無水硫酸鈉乾燥,過濾,旋轉減壓濃縮,所得殘留物(50.5mg)溶於乙腈中(40mL),加無水碳酸鉀(32.0mg),溴化苄(37.1mg),40℃反應5h。冷卻,過濾,通過管柱得化合物B-c1(63.1mg)。
2.2 化合物B-c2的合成
稱量化合物B-c1(63.1mg),溶於無水THF(10mL),冰浴冷卻,滴加1.0莫耳/公升(mol/L)n-BuLi的正己烷溶液(5.0mL),反應3h,滴加DMF(1.5mL),再反應3h。飽和氯化銨淬滅(5mL),乙酸乙酯萃取(10mL),吡啶
(10mL)洗滌。有機相用無水硫酸鈉乾燥,過濾,通過管柱得化合物B-c2(33.4mg)。
2.3 化合物B-c3的合成
稱量4-溴-3,5-二甲基苯酚(30.8mg),溶於二氯甲烷(50mL),加咪唑(18mg)。冷卻,滴加TIPSCl(25.5mg),反應5h。再加二氯甲烷(50mL)稀釋反應液,有機相分別用水(50mL)和吡啶(50mL)洗滌,無水硫酸鈉乾燥,旋轉減壓濃縮,通過管柱純化,得化合物B-c3(33.4mg)。
2.4 化合物B-c4的合成
稱量化合物B-c3(36.1mg),溶於THF(60mL),冰浴中冷卻,滴加1.0mol/L n-BuLi的正己烷溶液(4mL),反應3h後滴加化合物B-c2(33.4mg)的THF溶液(5mL),再反應3h,飽和氯化銨(20mL)淬滅,乙酸乙酯(20mL)萃取,吡啶(30mL)洗滌有機相,無水硫酸鈉乾燥,過濾,通過管柱得化合物B-c4(54.3mg)。
2.5 化合物B的合成
稱量化合物B-c4(54.3mg),溶解於THF(50mL),滴加1mol/L TBAF溶液(3mL),TLC顯示反應完成後加乙酸乙酯(50mL),水洗(20mL),吡啶
(20mL),無水硫酸鈉乾燥,過濾,旋轉減壓濃縮,得白色固體(23.3mg),溶解於DMF(5mL),冷卻,加入碳酸銫(40.4mg),再加溴乙酸苄酯(15.9mg)。40℃反應4h後反應液用MTBE稀釋(10mL),過濾,加水(20mL),水相用MTBE萃取(20mL*2),吡啶(20mL)洗滌合併的有機相。無水硫酸鈉乾燥,過濾,旋轉減壓濃縮,通過管柱,將其溶於醋酸中(5mL),加催化劑10% Pd/C(0.2g),室溫加氫反應過夜,過濾,旋轉減壓濃縮,通過管柱得淡黃色固體化合物B(15mg),化合物B的高解析度質譜圖如圖1所示。
3、GBL-0603的合成
3.1 GBL-0603-c1的合成
依次向反應瓶內加入DMF(3.0mL)、化合物B(15mg)、TBTU(8.47mg)和DIPEA(20.2mg),反應6h。然後迅速加入化合物A(47mg),室溫攪拌2h。HPLC檢測,反應合格,結束反應。
3.2 GBL-0603的合成
GBL-0603-c1反應液經HPLC中控檢測合格後,在冰浴條件下,用1.0mol/L的氨水溶液調反應液pH值為8-10。反應液pH值合格後,撤掉冰浴,室溫攪拌,反應半小時進行HPLC中控分析,反應合格,用冰醋酸調反應液pH值為7.0,反應液pH值合格後,進行濃縮,蒸除反應液中的DMF,濃縮殘物用
35%乙腈/水溶解,過濾、冷凍乾燥,得到29.47mg冷凍乾燥品,GBL-0603的高解析度質譜圖如圖2所示。
實施例2:GBL-0603對db小鼠脂質代謝作用影響的劑效研究
實驗動物與飼養:
選取30隻雄性7周齡(BKS-db)遺傳肥胖小鼠模型。實驗前小鼠需先適應環境一周,選擇健康小鼠作為受試動物。IVC籠具飼養,飼養密度為5隻/籠,每週更換兩次墊料。實驗動物房要求:室溫22至24℃,相對濕度40至70%,自動照明,12h明暗交替(08點00分開燈,20點00分關燈),實驗動物房標準符合中華人民共和國國家標準GB14925-2010。
藥物配製方法:
準確稱取GBL-0603 210mg,溶解於35mL溶劑中,配製成6mg/mL母液,各個劑量組依次使用該母液分別稀釋3倍、10倍、30倍、66.7倍後按相同的給藥劑量進行給藥。每三天配製一次GBL-0603母液。母液配製後於4℃保存備用。
實驗操作:
實驗開始前,採血檢測各組小鼠的總膽固醇(CHO),稱量體重根據體重隨機分組。給藥期間每日稱量小鼠體重。末次給藥後禁食6h,將各組小鼠安樂死,心臟採血,分離血清,檢測血清中三酸甘油酯(TG)、總膽固醇(CHO)、低密度脂蛋白(LDLC)、ALT和AST濃度。採血後,稱量肝臟重量,取各組小鼠肝臟中葉的一部分液態氮快速冷凍,-80℃保存備用。另外將小鼠肝臟中葉固定後石蠟包埋。取心臟並稱取心臟重量。檢測肝組織中CHO和TG的含量。進行肝組織病理學檢測:將全部小鼠進行切片及HE染色,對照用藥前後肝細胞脂肪變、炎症化和氣球樣化。
實施例3:添加促進劑癸酸鈉的藥效研究
試驗操作:
G2/G3/G4按照藥物重量計算好溶劑體積,加入溶劑,反復渦旋(vortex),溶解完全後使用。配製完成後,一小時內完成給藥。
實驗開始前,稱量體重根據體重隨機分組。末次給藥後禁食6h,將各組小鼠安樂死,心臟採血,分離血清,檢測血清中三酸甘油酯(TG)、總膽固醇(CHO)、低密度脂蛋白(LDLC),並檢測肝組織中CHO和TG的含量。
實施例4:GBL-0603和Kylo-0101對正常小鼠甲狀腺和肝酶的影響研究
試驗操作:
實驗開始前,稱量體重根據體重隨機分組。給藥期間每週一次稱量小鼠體重。末次給藥後禁食6h,將各組小鼠安樂死,心臟採血,分離血
清,檢測血清中空白組和GBL-0603給藥組的T3、fT3、T4、fT4、TSH的含量;骨密度、體重、肝臟和心臟重量;肝酶ALT、AST及GGT。檢測空白組和Kylo-0101給藥組的肝酶ALT、AST及GGT。
Claims (15)
- 如請求項1所述之具有甲狀腺激素受體激動劑特性的肝標靶化合物,其中,n為1至3的整數。
- 如請求項4所述之方法,其中,n為1至3的整數。
- 一種如請求項1至3中任一項所述之具有甲狀腺激素受體激動劑特性的肝標靶化合物在製備用於治療和/或預防由甲狀腺激素調節失調所引起之疾病的藥物中的用途。
- 如請求項6所述之用途,其中,所述疾病為代謝性疾病。
- 如請求項6所述之用途,其中,所述疾病為肥胖、高血脂症、高膽固醇血症、糖尿病、非酒精性脂肪性肝病、酒精性脂肪性肝病、動脈粥樣硬化、心血管疾病、甲狀腺功能減退或甲狀腺癌。
- 如請求項6所述之用途,其中,所述疾病為非酒精性脂肪性肝病。
- 如請求項6所述之用途,其中,所述疾病為非酒精性脂肪性肝炎或酒精性脂肪性肝炎。
- 一種用於治療和/或預防由甲狀腺激素調節失調所引起之疾病的藥物組合物,該藥物組合物包含治療有效量的如請求項1至3中任一項所述之具有甲狀腺激素受體激動劑特性的肝標靶化合物以及選擇性存在的藥學上可接受之賦形劑。
- 如請求項11所述之藥物組合物,其中,所述藥學上可接受之賦形劑包括腸道吸收促進劑,且所述腸道吸收促進劑為中鏈脂肪酸鈉鹽、膽酸鹽、環糊精、陽離子型聚合物、陰離子型聚合物或巰基化聚合物。
- 如請求項12所述之藥物組合物,其中,所述中鏈脂肪酸鈉鹽為癸酸鈉。
- 如請求項13所述之藥物組合物,其中,所述具有甲狀腺激素受體激動劑特性的肝標靶化合物與癸酸鈉的重量比為1:0.2至1:0.75。
- 如請求項11至14中任一項所述之藥物組合物,其中,所述藥物組合物的劑型為注射劑,或者為速釋或緩釋的口服製劑。
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CN111116684B (zh) | 2020-09-25 |
EP4086267A4 (en) | 2023-04-26 |
CN111116684A (zh) | 2020-05-08 |
WO2021135335A1 (zh) | 2021-07-08 |
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