CN114585383B - 包含rip激酶抑制剂的用于防脱发或促生发的组合物 - Google Patents
包含rip激酶抑制剂的用于防脱发或促生发的组合物 Download PDFInfo
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- CN114585383B CN114585383B CN202080072803.1A CN202080072803A CN114585383B CN 114585383 B CN114585383 B CN 114585383B CN 202080072803 A CN202080072803 A CN 202080072803A CN 114585383 B CN114585383 B CN 114585383B
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Abstract
本发明涉及包含RIP激酶(RIPK)抑制剂的用于防脱发或促生发的组合物,更详细地,涉及包含选自由低分子化合物、小干扰核糖核酸(siRNA)、短发夹核糖核酸(shRNA)或抗体组成的组中的一种以上的RIP激酶抑制剂的用于防脱发或促生发的组合物。
Description
技术领域
本发明涉及包含RIP激酶(RIPK)抑制剂的用于防脱发或促生发的组合物,更详细地,涉及包含选自由低分子化合物、小干扰核糖核酸(siRNA)、短发夹核糖核酸(shRNA)或抗体组成的组中的一种以上的RIP激酶抑制剂的用于防脱发或促生发的组合物。
背景技术
近来,随着对美容的关注提高,对脱发症的治疗的关注也随之日益高涨。所谓脱发症,是指正常应生长毛发的部位处于没有毛发的状态。毛发虽不涉及与生命直接相关的重要的生理功能,但从美容的观点来看,其作用非常大,此外,还与阻隔紫外光、保护头部等功能相关。若脱发严重,则会在社会生活方面出现问题,也会给心理上带来很大的影响,因此在生活质量方面非常重要。
脱发在临床上可以分为伴有伤痕的瘢痕性脱发与只脱发的非瘢痕性脱发。在瘢痕性脱发的情况下,毛囊被破坏而不再生发。毛发在称为毛囊的部位生成,各毛囊经过周期性地活动和静止的阶段。这种毛发周期的时间间隔取决于身体的不同部位,头发经过2年~6年左右的生长期(anagen)和2周~4周的退行期(catagen)后进入3个月~4个月左右的休止期(telogen)。各毛囊在人的一生具有10次~20次的毛囊生长周期(hair follicle growthcycle)。
现在,作为脱发治疗法最为常用的手术方法为自体毛发移植,广泛实施使用保法止及米诺地尔的药物治疗。在药物治疗的情况下,虽在给药的当时表现出生发的功效,但一旦中断治疗,则再次出现脱发,尤其,米诺地尔的情况下,具有性功能障碍等副作用。
另一方面,RIP激酶(RIP kinase;受体相互作用蛋白激酶(receptor-interactingprotein kinase),RIPK)为与先天免疫信号传递相关的TKL系列丝氨酸/苏氨酸蛋白激酶,在人类中存在RIPK1、RIPK2、RIPK3、RIPK4及RIPK5等5种RIP激酶。RIP激酶抑制剂主要为坏死抑制(韩国授权专利第10-1640068号)或者自身免疫治疗(韩国授权专利第10-1858346号)而研究,上述RIP激酶抑制剂与毛发生长相关的内容尚未公知。
尤其,已知为阻断RIP1/RIPK1途径的necrostatin-1及其衍生物(necrostatin-1s等)、西比利林(sibiriline)、GSK963或GSK2982772为对细胞坏死的基于色氨酸的小分子抑制剂,已知特异性地抑制坏死性凋亡(necroptosis),但有关它们促进毛发生长的效果尚处于未公知的状态。
于是,在本发明中,为了开发更为有效的用于预防及治疗脱发的组合物而努力的结果,确认到选自由低分子化合物、小干扰核糖核酸、短发夹核糖核酸或抗体组成的组中的一种以上的RIP激酶抑制剂不仅促进诱导毛发生长,还在小鼠中确认到显著增加生发的效果,从而完成本发明。
现有技术文献
专利文献
专利文献1:韩国授权专利公报第10-1640068号(2016年7月18日)
专利文献2:韩国授权专利公报第10-1858346号(2018年5月16日)
发明内容
技术问题
本发明的目的在于,提供包含RIP激酶抑制剂作为有效成分的用于防脱发或促生发的组合物。
技术方案
本发明提供包含RIP激酶抑制剂的用于防脱发或促生发的组合物。
并且,本发明涉及利用RIP激酶抑制剂来防止脱发或促进生发的方法。
在一实施方式中,上述RIP激酶抑制剂可以抑制RIPK1或RIPK3。
在一实施方式中,上述RIP激酶抑制剂可以为低分子化合物、小干扰核糖核酸、短发夹核糖核酸或抗体,但不限于此。
在本发明的一实施方式中,上述低分子化合物可以为下述化学式1的化合物或其药学上可接受的盐。
化学式1
在上述化学式中,R1可以为C1-C6烷基、C2-C6烯基或C2-C6炔基;R2可以为O或S;R3至R5可以为H、C1-C6烷基、C2-C6烯基、C2-C6炔基、芳基、杂芳基、环烷基或杂环烷基;R6可以各自独立地为卤素、烷氧基或羟基;X1至X4可以各自独立地为C或N;以及a可以为0至4的整数。
在一实施方式中,上述R1可以为C1-C6烷基;R3至R5可以为H;R6可以为卤素;X1至X4可以为C;以及a可以为0或1。
在再一实施方式中,上述低分子化合物可以为化学式2或化学式3的化合物或其药学上可接受的盐,下述化学式2的化合物表示为necrostatin-1,化学式3的化合物表示为necrostatin-1s。
化学式2
化学式3
在本发明的一实施方式中,上述低分子化合物可以为下述化学式4的化合物或其药学上可接受的盐。
化学式4
在上述化学式中,R可以为H、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤素、烷氧基、羟基、氰基、芳基、杂芳基、环烷基或杂环烷基。
在还有一实施方式中,上述低分子化合物可以为下述化学式5的化合物或其药学上可接受的盐。下述化学式5的化合物称为西比利林。
化学式5
在本发明的一实施方式中,上述低分子化合物可以为下述化学式6的化合物或其药学上可接受的盐。
化学式6
在上述化学式中,R1或R2可以各自独立地为H、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤素、烷氧基、羟基、氰基、芳基、杂芳基、环烷基或杂环烷基。
在一实施方式中,上述R1可以为芳基,R2可以为C1-C6烷基。
在另一实施方式中,上述低分子化合物可以为下述化学式7的化合物或其药学上可接受的盐,下述化学式7的化合物称为GSK963。
化学式7
在本发明的一实施方式中,上述低分子化合物可以为下述化学式8的化合物或其同分异构体或其药学上可接受的盐。
化学式8
在上述化学式中,R1或R2可以各自独立地为H、C1-C6烷基、C2-C6烯基、C2-C6炔基、卤素、烷氧基、羟基、氰基、芳基、杂芳基、环烷基或杂环烷基。
在一实施方式中,上述R1可以为芳基,R2可以为C1-C6烷基。
在又一实施方式中,上述低分子化合物可以为下述化学式9的化合物或其药学上可接受的盐。下述化学式9的化合物称为GSK2982772。
化学式9
在本发明的一实施方式中,上述小干扰核糖核酸可以为包含序列1及序列2的碱基序列对的小干扰核糖核酸或者包含序列3及序列4的碱基序列对的小干扰核糖核酸。
并且,本发明提供通过向脱发患者给药RIP激酶抑制剂来预防或治疗脱发的方法。在此情况下,RIP激酶抑制剂可以为上述的低分子化合物、小干扰核糖核酸、短发夹核糖核酸或抗体。
发明的效果
在本发明中确认到通过作为RIP激酶抑制剂的necrostatin-1、necrostatin-1s、西比利林、GSK963或GSK2982772显著增加小鼠刚毛的毛发生长诱导促进及小鼠生毛的效果。并且,确认到对RIP激酶的小干扰核糖核酸也促进毛发的生长,因此,本发明的RIP激酶抑制剂能够轻松用作用于防脱发或促生发的用途。
附图说明
图1示出向小鼠刚毛处理necrostatin-1或necrostatin-1s时的毛发生长诱导促进程度。
图2示出向去毛的小鼠涂敷necrostatin-1s后,长毛的状态((a)部分)及测量毛的重量的结果((b)部分)。
图3示出向小鼠刚毛处理西比利林时的毛发生长诱导促进程度。
图4示出向小鼠刚毛处理GSK963时的毛发生长诱导促进程度。
图5示出向小鼠刚毛处理GSK2982772时的毛发生长诱导促进程度。
图6示出向小鼠刚毛处理本发明的小干扰核糖核酸时的毛发生长诱导促进程度。
具体实施方式
以下,参照附图详细说明本申请的实施方式及实施例,以使本发明所属技术领域的普通技术人员能够轻松实施本发明。但本申请可以实现为多种形态,不限定于在此说明的实施方式及实施例。
在本说明书全文中,当提及某部分“包含”某结构要素时,若无特别反对的记载,则不表示排除其他结构要素,而是表示还可以包含其他结构要素。
本发明涉及包含RIP激酶抑制剂作为有效成分的用于防脱发或促生发的组合物。上述RIP激酶抑制剂可以为选自由低分子化合物、小干扰核糖核酸、短发夹核糖核酸或抗体组成的组中的一种以上,可以抑制RIPK1或RIPK3。
上述低分子化合物为分子量低的化合物,包含能够抑制与RIP激酶相关的基因的表达、转录或活性的化学物质。
若无其他明示,则本发明所使用的残基及取代基的定义具有下述定义,以本发明所属技术领域的普通技术人员通常理解的含义来使用。
在本说明书中,“烷基”为具有伯、仲、叔、季碳原子的烃,包括直链型、分枝型、环型或可以为它们的组合的饱和脂肪族基。例如,烷基可以具有1个至20个碳原子(即,C1-C20烷基)、1个至10个碳原子(即,C1-C10烷基)或1个至6个碳原子(即,C1-C6烷基)。适当的烷基的例可以有甲基(Me,-CH3)、乙基(Et,-CH2CH3)、1-丙基(n-Pr,正丙基,-CH2CH2CH3)、2-丙基(i-Pr,异丙基,-CH(CH3)2)、1-丁基(n-Bu,正丁基、-CH2CH2CH2CH3)、2-甲基-1-丙基(i-Bu,异丁基-CH2CH(CH3)2)、2-丁基(s-Bu,仲丁基、-CH(CH3)CH2CH3)、2-甲基-2-丙基(t-Bu,叔丁基,-C(CH3)3)、1-戊基(正戊基,-CH2CH2CH2CH2CH3)、2-戊基(-CH(CH3)CH2CH2CH3)、3-戊基(-CH(CH2CH3)2)、2-甲基-2-丁基(-C(CH3)2CH2CH3)、3-甲基-2-丁基(-CH(CH3)CH(CH3)2)、3-甲基-1-丁基(-CH2CH2CH(CH3)2)、2-甲基-1-丁基(-CH2CH(CH3)CH2CH3)、1-己基(-CH2CH2CH2CH2CH2CH3)、2-己基(-CH(CH3)CH2CH2CH2CH3)、3-己基(-CH(CH2CH3)(CH2CH2CH3))、2-甲基-2-戊基(-C(CH3)2CH2CH2CH3)、3-甲基-2-戊基(-CH(CH3)CH(CH3)CH2CH3)4-甲基-2-戊基(-CH(CH3)CH2CH(CH3)2)、3-甲基-3-戊基(-C(CH3)(CH2CH3)2)、2-甲基-3-戊基(-CH(CH2CH3)CH(CH3)2)、2,3-二甲基-2-丁基(-C(CH3)2CH(CH3)2)、3,3-二甲基-2-丁基(-CH(CH3)C(CH3)3)及辛基(-(CH2)7CH3),但不限定于此。
进而,说明书、实施例及发明要求保护范围全文中使用的术语“烷基”包括所有非取代或取代的烷基,其中,后者为具有包括三氟甲基及2,2,2-三氟乙基之类的卤代烷基等在内的,取代烃骨骼中的一个以上的碳原子上的氢的取代基的烷基残基。
在术语“Cx-y”或“Cx-Cy”与烷基、烯基或炔基之类的化学残疾一同使用时,应认为包含链内包含x个至y个碳原子的基。若C0烷基位于基的末端,则表示氢,若位于内部,则表示键合。例如,C1-C20烷基表示链内含有1个至20个碳原子。
“烯基”具有伯、仲、叔、或季碳原子,包括直链型、分枝型、环型基或它们的组合,为具有一个以上的不饱和区域,即,具有碳-碳sp2双键的烃。例如,烯基可以具有2个至20个碳原子(即,C2-C20的烯基)、2个至12个碳原子(即,C2-C12烯基)、2个至10个碳原子(即,C2-C10的烯基)或2个至6个碳原子(即,C2-C6烯基)。适当的烯基的例可以有乙烯基(-CH=CH2)、丙烯基(-CH2CH=CH2)、环戊烯基(-C5H7)及5-己烯基(-CH2CH2CH2CH2CH=CH2),但不限定于此。
“炔基”具有伯、仲、叔、或季碳原子,包括直链型、分枝型、环型基或它们的组合,为具有一个以上的碳-碳sp三键的烃。例如,炔基可以具有2个至20个碳原子(即,C2-C20炔基)、2个至12个碳原子(即,C2-C12炔基)、2个至10个碳原子(即,C2-C10炔基)或2个至6个碳原子(即,C2-C6炔基)。适当的炔基的例可以有乙炔基(-C≡CH)及丙炔基(-CH2C≡CH),但不限定于此。
本说明书中所使用的术语“卤素”包括氯、氟、溴及碘。
“环烷基”可以为单环、双环或多环,是指环的原子分别为碳的非芳香族饱和或不饱和的1价或2价的环。当环烷基为单环时,可以具有3个至7个碳原子,为双环时,可以具有7个至12个碳原子,为多环时,可以具有20个以下的碳原子。
“杂环烷基”是指上述环烷基的环结构包含一个以上的杂原子,优选地,包含1个至4个杂原子,更优选地,包含1个至2个杂原子。适当的杂原子的例可以包括氧、硫及氮。
“芳基”包括环的原子分别为碳的单环、双环或多环的1价或2价的芳香族烃基。芳基环可以具有6元至20元的环,优选地,可以具有6元至14元的环。
“杂芳基”是指环内含有一个以上的杂原子的单环、双环或多环的1价或2价的芳香族基。适当的杂原子的例可例举氧、硫及氮。
在本发明中,“小干扰核糖核酸(siRNA)”是指能够通过特定信使核糖核酸(mRNA)的切割(cleavage)来诱导核糖核酸干扰(RNAi,RNA interference)现象的短的双链核糖核酸(RNA)。小干扰核糖核酸由具有与目标基因相同的序列的正义核糖核酸链和具有与之互补的序列的反义核糖核酸链构成。由于小干扰核糖核酸能够抑制目标基因的表达,因此通过有效的基因敲低(knock-down)方法或基因治疗(gene therapy)的方法提供。
小干扰核糖核酸不限于核糖核酸之间形成配对的双链核糖核酸部分完全形成对的情况,可以通过误配(mismatch,对应的碱基不是互补的)、隆起(bulge,一方的链上没有对应的碱基)等方式包含不形成对的部分的一部分。总长度为10碱基至100碱基,优选为15碱基至80碱基,更优先为20碱基至70碱基。小干扰核糖核酸末端结构只要是能够通过核糖核酸干扰效果抑制目标基因的表达,无论是平滑(blunt)末端还是黏性(cohesive)末端都可以。黏性末端结构可以为在3'末端处突出的结构或者在5'末端处突出的结构。突出的碱基数不受限制。例如,碱基数可以为1个碱基至8个碱基,优选地看可以为2个碱基至6个碱基。
并且,在能够保持目标基因表达的抑制效果的范围内,例如小干扰核糖核酸可以在一侧末端的突出部分包含低分子核糖核酸(例如,转运核糖核酸(tRNA)、核糖体核糖核酸(rRNA)、病毒核糖核酸之类的天然核糖核酸分子或者人造核糖核酸分子)。小干扰核糖核酸的末端结构没必要在两侧都具有切割结构,也可以为双链核糖核酸的一方的末端部位通过衔接物核糖核酸(linker RNA)连接的茎环(主干-循环(stem-loop))型结构。衔接物的长度只要是不给形成主干部分的对带来影响的就不受特别限制。
制备小干扰核糖核酸的方法有在实验室内直接合成小干扰核糖核酸后,经过转化(transfection)过程导入细胞内的方法,以及为了使小干扰核糖核酸在细胞内表达而将制备的小干扰核糖核酸(siRNA)表达载体或聚合酶链式反应获得的(PCR-derived)小干扰核糖核酸表达盒向细胞内转化或感染(infection)的方法。制备小干扰核糖核酸并导入细胞或动物的方法的确定可以根据实验的目的及目标基因产物的细胞生物学功能而变化。
在本发明中,“短发夹核糖核酸(shRNA)”是指小发夹核糖核酸(small hairpinRNA)或者短发夹核糖核酸(short hairpin RNA,shRNA)),是在通过核糖核酸干扰使基因的表达沉默(silencing)时所使用的的具有小的发夹(hairpin)结构的核糖核酸。短发夹核糖核酸利用载体向细胞导入,短发夹核糖核酸的发夹结构在细胞内通过其他物质被切割为小干扰核糖核酸,该小干扰核糖核酸与核糖核酸诱导沉默复合物(RNA induced silencingcomplex,RISC)结合,该复合物(complex)与具有与小干扰核糖核酸的序列相配的部分的信使核糖核酸结合来切割该信使核糖核酸,结果导致信使核糖核酸被破坏而引起信使核糖核酸所携带的基因不表达的基因沉默。
本发明的特征在于,上述小干扰核糖核酸为由序列1及序列2的碱基序列对构成的小干扰核糖核酸或由序列3及序列4的碱基序列对构成的小干扰核糖核酸,但也可以包含与上述小干扰核糖核酸的碱基序列相同90%以上、93%以上、95%以上、96%以上、97%以上、98%以上、99%以上的序列。
优选地,上述小干扰核糖核酸的特征在于抑制RIPK1或RIPK3基因的表达,但不限定于此,也可以抑制除RIPK1或RIPK3以外的其他RIP激酶相关基因的表达。
上述“抗体”可以与RIP激酶特异性结合来抑制RIP激酶活性,上述抗体不仅可以为具有2个全长的轻链及2个全长的重链的完全形态,还可以使用抗体分子的片段。抗体分子的片段是指保有肽标签(表位,epitope)结合功能的片段,包括单链Fv(scFv)、Fab、F(ab')、F(ab')2及单结构域(single domain)等。
本发明的组合物可以制备为药物组合物、准药品组合物或化妆品组合物。
在将本发明的组合物制备为药物组合物的情况下,本发明的药物组合物包含药学上可接受的载体。本发明的药物组合物所包含的药学上可接受的载体为通常使用的,包括乳糖、葡萄糖、蔗糖、山梨糖醇、甘露糖醇、淀粉、阿拉伯胶、磷酸钙、海藻酸盐、明胶、硅酸钙、微晶纤维素、聚乙烯吡咯烷酮、纤维素、水、糖浆、甲基纤维素、羟基苯甲酸甲酯、羟基苯甲酸丙酯、滑石、硬脂酸镁,矿物油等,但不限定于此。除上述成分以外,本发明的药物组合物还可以包含润滑剂、湿润剂、甜味剂、香味剂、乳化剂、悬浮剂、保存剂等。
本发明的药物组合物可以根据本发明所属技术领域的普通技术人员可以轻松实施的方法,可以利用药学上可接受的载体和/或赋形剂来配制,可以制备为单位剂量形态或者制备为放入多剂量容器内的形态。在此情况下,剂型可以为油或者水性介质中的溶液、悬浮液、糖浆剂或乳化液形态,也可以为提取剂、散剂、粉末剂、颗粒剂、片剂或胶囊剂形态,还可以包括分散剂或稳定剂。
在将本发明的组合物制备为准药品组合物的情况下,可以直接加入表现出防脱发或促生发效果的上述RIP激酶抑制剂,或者可以与其他准药品或准药品成分一同使用,可以根据通常的方法适当地使用。
本发明的用于防脱发或促生发的准药品组合物不特别限制其剂型,可以多种多样地配制为表现出防脱发或促生发效果的本发明所属技术领域公知的准药品的形态。上述配制的准药品有护发素、护发乳、护发膏、护发喷雾、摩丝、发胶、护发素、洗发水、护发素、发膜、焗油膏、眉毛生发剂、睫毛生发剂、睫毛滋养剂、宠物洗发水、宠物用护发素、洗手液、洗衣皂、肥皂、消毒剂、湿纸巾、面膜、药膏、化妆片或过滤器填充物,包括所有通常意义的准药品。
并且,在各剂型中,用于防脱发或促生发的准药品组合物可以根据其他准药品的剂型或使用目的等任意的选择其他成分来配合。
在将本发明的组合物制备为化妆品组合物的情况下,本发明的化妆品组合物所包含的成分除作为有效成分的上述RIP激酶抑制剂以外,还包含化妆品组合物通常使用的成分,例如包含抗氧化剂、稳定剂、溶解剂、维生素、颜料及香料之类的通常的辅助剂,还包含载体。
本发明的化妆品组合物可以制备为本发明所属技术领域通常制备的任意剂型,例如,可以配制为溶液、悬浮液、乳浊液、糊剂、凝胶、霜剂、乳剂、化妆粉、香皂、含表面活性剂的洗剂、油剂、粉状粉底、乳浊液粉底、蜡粉底及喷剂等,但不限定于此。
以下,将通过实施例更为详细地说明本发明,但下述实施例仅用于说明的目的,而不是限定本发明的范围。
实施例1
确认处理necrostatin-1或necrostatin-1s的毛发生长诱导效果
为了确认处理作为RIP激酶抑制剂的necrostatin-1(Nec-1,化学式2)或necrostatin-1s(Nec-1s,化学式3)的毛发生长诱导效果,将下述灭活型necrostatin-1(Nec-1i,化学式10)作为对照组进行实验。
化学式10
使用上述灭活型necrostatin-1和本发明的necrostatin-1及necrostatin-1s处理小鼠的刚毛(vibrissae)来确认毛发生长诱导程度。
具体地,整理C57BL/6雌性小鼠的刚毛进行器官培养(organ culture)。将整理的刚毛在48孔培养板中以每孔1根的方式进行培养,分为无处理组、灭活型necrostatin-1处理组、necrostatin-1处理组及necrostatin-1s处理组共4个组,向3个处理组的刚毛分别处理10μM后,在37℃的培养器中培养3天,结果如图1所示。
如图1所示,确认到相比于灭活型necrostatin-1,necrostatin-1及necrostatin-1s具有优秀的毛发生长促进效果。
实施例2
确认处理necrostatin-1s的生发效果
使用去毛机器剪短10只出生6周龄的雄性C3H/HeN小鼠的毛,使用去毛剂完全去除剩余的毛后,稳定1天后用于实验。
按照下述条件以每组5只小鼠的方式分组来进行实验。
(i)无处理对照组
(ii)2%米诺地尔(MNX,minoxidil)给药组
(iii)10μM的necrostatin-1s给药组
(iv)100μM的necrostatin-1s给药组
在13天内以100μl的量向上述不同组的小鼠的背部共涂敷13次,观察13天期间上述小鼠背部的发毛程度。13天后,使用刮脸刀片刮下发毛的小鼠背部的毛后,测量获得的毛的重量,结果如图2所示。
如图2所示,确认到necrostatin-1s给药组与无处理对照组相比,表现出优秀的毛发生长效果。尤其,确认到100μM的necrostatin-1s给药组与市面上出售的米诺地尔给药组相比,具有更为优秀的毛发生长诱导效果。
实施例3
确认处理西比利林的毛发生长诱导效果
为了确认处理作为RIP激酶抑制剂的西比利林(sibiriline,化学式5)的毛发生长诱导效果,使用西比利林处理小鼠的刚毛来确认毛发生长诱导程度。
具体地,整理C57BL/6雌性小鼠的刚毛进行器官培养。将整理的刚毛在48孔培养板中以每孔1根的方式进行培养,分为无处理组(对照组)、1μM的西比利林处理组及10μM的西比利林处理组共3个组并分别处理刚毛后,在37℃的培养器中培养3天,结果如图3所示。
如图3所示,确认到1μM的西比利林处理组及10μM的西比利林处理组都具有优秀的毛发生长促进功效。
实施例4
确认处理GSK963的毛发生长诱导效果
为了确认处理作为RIP激酶抑制剂的GSK963(化学式7)的毛发生长诱导效果,使用GSK963处理小鼠的刚毛来确认毛发生长诱导程度。
具体地,整理C57BL/6雌性小鼠的刚毛进行器官培养。将整理的刚毛在48孔培养板中以每孔1根的方式进行培养,分为无处理组(对照组)、1μM的GSK963处理组及10μM的GSK963处理组共3个组并分别处理刚毛后,在37℃的培养器中培养3天,结果如图4所示。
如图4所示,确认到1μM的GSK963处理组及10μM的GSK963处理组都具有优秀的毛发生长促进功效。
实施例5
确认处理GSK2982772的毛发生长诱导效果
为了确认处理作为RIP激酶抑制剂的GSK2982772(化学式9)的毛发生长诱导效果,使用GSK2982772处理小鼠的刚毛来确认毛发生长诱导程度。
具体地,整理C57BL/6雌性小鼠的刚毛进行器官培养。将整理的刚毛在48孔培养板中以每孔1根的方式进行培养,分为无处理组(对照组)、1μM的GSK2982772处理组、10μM的GSK2982772处理组及50μM的GSK2982772处理组共4个组并分别处理刚毛后,在37℃的培养器中培养3天,结果如图5所示。
如图5所示,确认到1μM的GSK2982772处理组、10μM的GSK2982772处理组及50μM的GSK2982772处理组都具有优秀的毛发生长促进功效。
实施例6
确认处理对RIP激酶的小干扰核糖核酸的毛发生长诱导效果
为了确认处理能够抑制RIP激酶表达的小干扰核糖核酸的毛发生长诱导效果,按照下述表1所示的合成小干扰核糖核酸,作为对照组的control小干扰核糖核酸是从(株)Bioneer公司购买来使用的。
表1
RIP激酶表达抑制小干扰核糖核酸序列
使用上述表1的小干扰核糖核酸处理小鼠的刚毛来确认毛发生长诱导程度。
具体地,整理C57BL/6雌性小鼠的刚毛进行器官培养。将整理的刚毛在48孔培养板中以每孔1根的方式进行培养,分为表1的RIPK1小干扰核糖核酸处理组、RIPK3小干扰核糖核酸处理组及control小干扰核糖核酸处理组(对照组)共3个组并分别处理刚毛后,在37℃的培养器中培养3天,结果如图6所示。
如图6所示,确认到通过处理RIPK1小干扰核糖核酸及RIPK3小干扰核糖核酸促进毛发生长。
从上述实验结果可知通过抑制RIP激酶表达促进毛发生长,可知除本发明使用的小干扰核糖核酸以外,其他RIP激酶抑制剂也具有防脱发或促生发的效果。
序列表
<110> 斯特莫尔有限公司
<120> 包含RIP激酶抑制剂的用于防脱发或促生发的组合物
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Claims (8)
1.组合物在制备用于促生发的药物中的用途,其特征在于,所述组合物包含下述化学式1的化合物或其药学上可接受的盐:
化学式1:
,
在上述化学式中,
R1为C1-C6烷基;
R2为O或S;
R3至R5为H;
R6为卤素;
X1至X4为C;以及
a为0或1。
2.根据权利要求1所述的组合物在制备用于促生发的药物中的用途,其特征在于,所述组合物包含下述化学式2或化学式3的化合物或其药学上可接受的盐:
化学式2:
;
化学式3:
。
3.组合物在制备用于促生发的药物中的用途,其特征在于,所述组合物包含下述化学式4的化合物或其药学上可接受的盐:
化学式4:
,
在上述化学式中,
R为羟基。
4.组合物在制备用于促生发的药物中的用途,其特征在于,所述组合物包含下述化学式6的化合物或其药学上可接受的盐:
化学式6:
,
在上述化学式中,
R1为苯基;以及
R2为C1-C6烷基。
5.根据权利要求4所述的组合物在制备用于促生发的药物中的用途,其特征在于,所述组合物包含下述化学式7的化合物或其药学上可接受的盐:
化学式7:
。
6.组合物在制备用于促生发的药物中的用途,其特征在于,所述组合物包含下述化学式8的化合物或其药学上可接受的盐:
化学式8:
,
在上述化学式中,
R1为苯基;以及
R2为C1-C6烷基。
7.根据权利要求6所述的组合物在制备用于促生发的药物中的用途,其特征在于,所述组合物包含下述化学式9的化合物或其药学上可接受的盐:
化学式9:
。
8.组合物在制备用于促生发的药物中的用途,其特征在于,所述组合物包含小干扰核糖核酸,所述小干扰核糖核酸的序列如SEQ NO: 1和SEQ NO: 2所示,或者如SEQ NO: 3和SEQ NO: 4所示。
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KR20190129125 | 2019-10-17 | ||
KR10-2019-0129125 | 2019-10-17 | ||
KR1020200020639A KR20210045908A (ko) | 2019-10-17 | 2020-02-19 | Rip 키나아제 억제제를 포함하는 탈모 방지 또는 발모 촉진용 조성물 |
KR10-2020-0020639 | 2020-02-19 | ||
KR10-2020-0101144 | 2020-08-12 | ||
KR1020200101144A KR102268702B1 (ko) | 2019-10-17 | 2020-08-12 | Rip 키나아제 억제제를 포함하는 탈모 방지 또는 발모 촉진용 조성물 |
PCT/KR2020/014074 WO2021075870A1 (ko) | 2019-10-17 | 2020-10-15 | Rip 키나아제 억제제를 포함하는 탈모 방지 또는 발모 촉진용 조성물 |
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