CN116574169B - 氘代gip/glp-1/gcg多受体激动剂药物及用途 - Google Patents
氘代gip/glp-1/gcg多受体激动剂药物及用途 Download PDFInfo
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- BTSOGEDATSQOAF-SMAAHMJQSA-N tirzepatide Chemical compound CC[C@H](C)[C@@H](C(N[C@@H](C)C(N[C@@H](CCC(N)=O)C(N[C@@H](CCCCNC(COCCOCCNC(COCCOCCNC(CC[C@H](C(O)=O)NC(CCCCCCCCCCCCCCCCCCC(O)=O)=O)=O)=O)=O)C(N[C@@H](C)C(N[C@@H](CC1=CC=CC=C1)C(N[C@@H](C(C)C)C(N[C@@H](CCC(N)=O)C(N[C@@H](CC1=CNC2=C1C=CC=C2)C(N[C@@H](CC(C)C)C(N[C@@H]([C@@H](C)CC)C(N[C@@H](C)C(NCC(NCC(N(CCC1)[C@@H]1C(N[C@@H](CO)C(N[C@@H](CO)C(NCC(N[C@@H](C)C(N(CCC1)[C@@H]1C(N(CCC1)[C@@H]1C(N(CCC1)[C@@H]1C(N[C@@H](CO)C(N)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)NC([C@H](CCCCN)NC([C@H](CC(O)=O)NC([C@H](CC(C)C)NC(C(C)(C)NC([C@H]([C@@H](C)CC)NC([C@H](CO)NC([C@H](CC(C=C1)=CC=C1O)NC([C@H](CC(O)=O)NC([C@H](CO)NC([C@H]([C@@H](C)O)NC([C@H](CC1=CC=CC=C1)NC([C@H]([C@@H](C)O)NC(CNC([C@H](CCC(O)=O)NC(C(C)(C)NC([C@H](CC(C=C1)=CC=C1O)N)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O BTSOGEDATSQOAF-SMAAHMJQSA-N 0.000 description 1
- 208000001072 type 2 diabetes mellitus Diseases 0.000 description 1
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Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/575—Hormones
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/04—Anorexiants; Antiobesity agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K38/00—Medicinal preparations containing peptides
Abstract
本发明公开了一种氘代GIP/GLP‑1/GCG多受体激动剂,如下式Ⅰ所示,本发明涉及氘代GIP/GLP‑1/GCG多受体激动剂、其药物组合物及用途。本发明所述氘代GIP/GLP‑1/GCG多受体激动剂药物,能进一步改善GIP和GLP‑1双受体激动剂的药代动力学性质,降低给药剂量和可能的毒副作用。
Description
技术领域
本发明属于生物医药领域,具体涉及氘代GIP/GLP-1/GCG多受体激动剂及用途。
背景技术
GLP-1R属于7次跨膜的G蛋白偶联受体B家族中的胰岛血糖系受体亚家族,表达于胰腺或胰腺外组织,包括中枢神经系统、心血管、胃肠道等。人胰腺组织高表达GLP-1R,GLP-1可与GLP-1R结合可促进胰岛素的合成与分泌,并刺激胰岛β细胞的增殖、抑制其凋亡。GLP-1受体激动剂可以刺激人体胰岛素分泌,且降解速度较慢,并具备降低体重,改善血脂、降低血压的临床作用。GIP是一个单链的肽类激素,它由42个氨基酸残基组成的一个多肽分子,是进餐后,由小肠中的十二指肠、空肠的肠黏膜的K细胞分泌。胰高血糖素(Glucagon Gcg)由胰岛α细胞分泌,能够抑制胰岛素的分泌并促进肝糖原的分解,从而升高血糖。此外,胰高血糖素还具有促进分解代谢和产热的作用。激动Gcg受体造成的升糖作用,可以被激动GLP-1受体带来的葡萄糖浓度依赖性促进胰岛素分泌作用和抑制胰高血糖素分泌作用所对抗,而激动Gcg受体带来的能量分解作用与激动GLP-1受体带来的减少进食作用,二者之间可相互协同降低体重。Retatrutide(LY3437943)是礼来基于GIP肽序开发的一种靶向GLP-1R/GCGR/GIPR的多肽药物,人体内平均半衰期长达6天,小鼠体内半衰期为21h(0.47mg/kg),Retatrutide治疗肥胖的2期临床试验结果显示,与安慰剂相比,所有剂量的Retatrutide治疗均显示出具有临床意义的体重减轻,每周注射Retatrutide(12 mg),48周后患者平均体重减轻24.2%, 这是迄今为止药物减肥能达到的最好效果。
氘代药物,既将药物分子的一个或多个碳氢键用碳氘键替代的新药物分子,可以通过改善原有药物的药代动力学性质,进而克服药物原有的易于代谢、副作用较大等缺陷。
本发明为氘代GIP/GLP-1/GCG多受体激动剂药物,可以进一步改善目前GIP/GLP-1/GCG多受体激动剂Retatrutide的药代动力学性质,降低给药剂量和可能的毒副作用。
发明内容
本发明提供的氘代GIP/GLP-1/GCG多受体激动剂及其药学上可接受的盐,可以进一步改善氘代GIP/GLP-1/GCG多受体激动剂Tirzepatide的药代动力学性质,降低给药剂量和可能的毒副作用。
为了实现上述目的,如本发明所述一种如下式Ⅰ所示的氘代GIP/GLP-1/GCG多受体激动剂及其药学上可接受的盐:
其中,R1, R2, R3, R4独立地选自H或氘,且R1, R2, R3, R4不同时为H。
进一步本发明所述氘代GIP/GLP-1/GCG多受体激动剂,其结构为:
本发明所述氘代GIP/GLP-1/GCG多受体激动剂及其药学上可接受的盐,其药学上可接受的盐选自甲磺酸盐、马来酸盐、盐酸盐或磷酸盐。
本发明所述的氘代GIP/GLP-1/GCG多受体激动剂及其药学上可接受的盐,包括其在治疗二型糖尿病、肥胖或超重以及与体重相关合并症的应用。。
本发明所述的氘代GIP/GLP-1/GCG多受体激动剂及其药学上可接受的盐,包括氘代GIP/GLP-1/GCG多受体激动剂及其药学上可接受的盐作为活性成分和药学上可接受的载体组成。
本发明所述的氘代GIP/GLP-1/GCG多受体激动剂化合物及其药学上可接受盐的药物组合物,所述药物组合物选自胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。
有益效果:与现有技术相比,本发明具有如下优点:
本发明提供一类氘代GIP/GLP-1/GCG多受体激动剂药物,进一步改善GIP和GLP-1双受体激动剂的药代动力学性质,降低给药剂量和可能的毒副作用。
具体实施方式
以下结合实施例对本发明作进一步说明,但并不因此将本发明限制在所述的实施例范围之中。下列实施例中未注明具体条件的实验方法,按照常规方法和条件,或按照商品说明书选择。
固相合成一般方法
固相氨基酸的合成均在固相自动肽合成仪上进行。使用rinkamide-AM树脂(Merrifield聚合物负载(2 ,4-二甲氧基苯基) (4-烷氧基苯基)甲烷,其中4-烷氧基为与树脂连接的位置和化学键类型,负载量0 .7mmol/g)。使用DMF和DCM溶解反应所用试剂。反应中所用的溶剂和试剂为:DMF=N, N-二甲基甲酰胺;DCM=二氯甲烷;HATU=1-[二(二甲胺基)亚甲基]-3-氧代-1H-1 ,2 ,3-三氮唑并[4 ,5-b]吡啶六氟磷酸盐;DIPEA=二异丙基乙胺。使用所需氨基酸(0.6mmol)、HATU(0.6mmol),DIPEA(1.2mmol)、DMF(6mL)在25℃条件下进行反应。
完成所需直链肽合成后,将树脂再用无水DMF洗涤1次,后抽至干。向干燥的树脂加入切割液(三氟乙酸:硫代苯甲醚:1 ,2-乙二硫醇:苯甲醚=90:5:2 .5:2 .5,体积比)。混合物在10℃下振摇3小时。反应结束后,将切割液抽滤,浓缩至原体积1/5,浓缩液逐滴加入到10倍体积的-20℃无水乙醚中。将所得的粗品肽溶于一定量的纯净水中,使用三乙胺或2MHCl调节PH至7,加入乙腈至澄清,冻干得粗品固体。加入一定量的乙腈使其完全溶解,经0.33μM滤器过滤。使用Aglient Eclipase XDB-C18柱进行分离,流动相A:0.1%TFA/H2O;流动相B:0.1%TFA/MeCN。色谱条件为10%B-100%B,20min。
非天然氨基酸合成:
中间体1合成
将甘氨酸(3mmol)和邻羟基苯甲醛(0.45mmol)用氘代醋酸(10mL)溶解,氮气保护下于100℃搅拌反应两小时后,降温至室温,浓缩溶剂后,加入2mL重水,室温继续搅拌15min。浓缩后,加入甲醇打浆,过滤干燥后得到中间体1。
中间体2合成
将中间体1(1mmol)溶于13mL丙酮,并缓慢加入13mL10%碳酸钠水溶液,0℃条件下加入Fmoc-OSu(1.5mmol),搅拌5min后,移至室温反应24小时,TLC监测反应完全后,加入2M盐酸调节pH至2-3,加入乙酸乙酯萃取3次,水洗2次,饱和食盐水洗1次,浓缩有机相,经柱层析(二氯甲烷:甲醇=100:1)得中间体2。
实施例1:目标化合物1的制备
使用rinkamide-AM树脂(Merrifield聚合物负载(2 ,4-二甲氧基苯基) (4-烷氧基苯基)甲烷,其中4-烷氧基为与树脂连接的位置和化学键类型,负载量0 .7mmol/g)。使用DMF和DCM溶解反应所用试剂。反应中所用的溶剂和试剂为:DMF=N, N-二甲基甲酰胺;DCM=二氯甲烷;HATU=1-[二(二甲胺基)亚甲基]-3-氧代-1H-1,2,3-三氮唑并[4,5-b]吡啶六氟磷酸盐;DIPEA=二异丙基乙胺。使用所需氨基酸(0.6mmol)、HATU(0.6mmol),DIPEA(1.2mmol)、DMF(6mL)在25℃条件下进行反应。
完成所需直链肽合成后,将树脂再用无水DMF洗涤1次,后抽至干。向干燥的树脂加入切割液(三氟乙酸:硫代苯甲醚:1 ,2-乙二硫醇:苯甲醚=90:5:2 .5:2 .5,体积比)。混合物在10℃下振摇3小时。反应结束后,将切割液抽滤,浓缩至原体积1/5,浓缩液逐滴加入到10倍体积的-20℃无水乙醚中。将所得的粗品肽溶于一定量的纯净水中,使用三乙胺或2MHCl调节PH至7,加入乙腈至澄清,冻干得粗品固体。加入一定量的乙腈使其完全溶解,经0.33μM滤器过滤。使用Aglient Eclipase XDB-C18柱进行分离,流动相A:0.1%TFA/H2O;流动相B:0.1%TFA/MeCN。色谱条件为10%B-100%B,20min。使用LC/MS确认了化合物结构正确(LC/MS: [(M+4H)/4]+=1185.7)。
实施例2:目标化合物2的制备
参考实施例1 的合成方法制备,使用LC/MS确认了化合物结构正确,LC/MS: [(M+4H)/4]+=1185.4。
实施例3:目标化合物3的制备
参考实施例1 的合成方法制备,使用LC/MS确认了化合物结构正确,LC/MS: [(M+4H)/4]+=1188.4。
试验例1:化合物1-3对HEK293细胞cAMP活性测试
通过测量HEK293细胞中的细胞内cAMP来证明在本发明实施例化合物1-3存在下的hGLP-1R、GlucagonR、GIP-R功能活性。将HEK293细胞在完全培养基中传代,在大约48小时增殖后,在细胞测定当天,用含有0.5%FBS的Invitrogen 31053DMEM交换冷冻培养基。将本发明的化合物溶于DMSO中,在37℃处理时间为30分钟。最终的DMS0浓度不超过1.1%,最终的IBMX浓度为250μΜ。通过均相时间分辨荧光技术(Cisbio Bioassays,Bedford,MA),使用Dynamic 2测定法测量环AMP。相应cAMP浓度由比值计算法和外部标准推出。使用四参数逻辑斯蒂方程,检验测试化合物的S形剂量反应,并与天然C18酰化配体进行比较。
表1. HEK293细胞中GLP-1R功能活性测定
化合物编号 | EC50 (nM) |
化合物1 | 0.6 |
化合物2 | 0.7 |
化合物3 | 0.5 |
Retatrutide | 1.2 |
表2. HEK293细胞中GIP-R功能活性测定
化合物编号 | EC50 (nM) |
化合物1 | 0.3 |
化合物2 | 0.3 |
化合物3 | 0.4 |
Retatrutide | 1.0 |
表3. HEK293细胞中GlucagonR功能活性测定
化合物编号 | EC50 (nM) |
化合物1 | 1.7 |
化合物2 | 3.0 |
化合物3 | 2.1 |
Retatrutide | 6.0 |
表1-3结果显示,本发明实施例化合物1-3存在下的hGLP-1R、GlucagonR、GIP-R功能活性相对于Retatrutide更好。
试验例2:化合物的药代动力学实验
(一)实验仪器和材料
高速冷冻离心机,涡旋振荡器(Vortex Genius3),高速离心机( Eppendorf5415D), 一次性使用注射器,移液枪(Eppendorf),实验所用SD雄性大鼠均购自扬州大学,EDTA-K2真空采血管,生理盐水。所有口服组大鼠在给药前禁食12h,自由饮水,给药期间自由进水和进食。
(二)实验步骤
将说明书中所述中间体1和实施例1化合物1使用DMSO/solutol/water(10/10/80)溶解制成澄清溶液,皮下注射给药化合物的剂量为0.5 mg/kg。于皮下给药后的2 min, 10min, 30 min, 1 h, 2 h, 3 h, 5 h, 8 h, 12 h, 16 h, 24 h,从眼底静脉丛连续取血0.5 mL至肝素管中,从眼底静脉丛连续取血0.5 mL肝素管中。将样品在8000 r,4℃条件下离心10 min后,取上层血浆0.15 mL,-20℃条件下保存,之后进行LC-MS/MS分析。数据通过WinNolin非房室模型分析,得到关键药代动力学参数。
(三)实验结果
表4药代动力学参数
Parameter | Retatrutide | 化合物1 |
t1/2 (h) | 21 | 30 |
Tmax (h) | 12 | 13 |
由此可见,表4结果显示:相对于Retatrutide,化合物1口服给药的半衰期提高明显,可以有效改进给药剂量,从而降低高剂量给药的毒副作用。
最后有必要说明的是,以上对本发明的具体实施例进行了详细描述,但其只作为范例,本发明并不限制于以上描述的具体实施例。对于本领域技术人员而言,任何对本发明进行的等同修改和替代也都在本发明的范畴之中。因此,在不脱离本发明的精神和范围下所作的均等变换和修改,都应涵盖在本发明的范围内。
Claims (5)
1.一种氘代GIP/GLP-1/GCG多受体激动剂及其药学上可接受的盐,其特征在于,所述氘代GIP/GLP-1/GCG多受体激动剂选自以下化合物中的任一种:
2.根据权利要求1所述的氘代GIP/GLP-1/GCG多受体激动剂及其药学上可接受的盐,其特征在于,所述药学上可接受的盐选自甲磺酸盐、马来酸盐、盐酸盐或磷酸盐。
3.权利要求1所述的氘代GIP/GLP-1/GCG多受体激动剂及其药学上可接受的盐在制备治疗二型糖尿病、肥胖或超重或与体重相关合并症的药物中的应用。
4.一种药物组合物,其特征在于,所述药物组合物由权利要求1所述氘代GIP/GLP-1/GCG多受体激动剂及其药学上可接受的盐和药学上可接受的载体组成。
5.根据权利要求4所述的药物组合物,其特征在于,所述药物组合物选自胶囊剂、散剂、片剂、颗粒剂、丸剂、注射剂、糖浆剂、口服液、吸入剂、软膏剂、栓剂或贴剂。
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Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022078259A1 (zh) * | 2020-10-12 | 2022-04-21 | 四川百利药业有限责任公司 | 一种氘代的喜树碱衍生物及其抗体药物偶联物 |
WO2022247701A1 (zh) * | 2021-05-26 | 2022-12-01 | 联邦生物科技(珠海横琴)有限公司 | 多激动剂及其应用 |
CN115850179A (zh) * | 2022-12-13 | 2023-03-28 | 北京科翔中升医药科技有限公司 | 一种氘代吲唑类mapk抑制剂药物及用途 |
CN116143884A (zh) * | 2023-02-03 | 2023-05-23 | 江苏师范大学 | 一类长效GLP-1/glucagon/GIP受体三重激动剂及其应用 |
CN116162081A (zh) * | 2022-12-13 | 2023-05-26 | 药康众拓(江苏)医药科技有限公司 | 一类氘代吡啶酰胺类ccr6抑制剂药物及用途 |
CN116283997A (zh) * | 2022-09-08 | 2023-06-23 | 药康众拓(江苏)医药科技有限公司 | 氘代hgfr抑制剂药物及用途 |
-
2023
- 2023-07-10 CN CN202310839606.3A patent/CN116574169B/zh active Active
Patent Citations (6)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2022078259A1 (zh) * | 2020-10-12 | 2022-04-21 | 四川百利药业有限责任公司 | 一种氘代的喜树碱衍生物及其抗体药物偶联物 |
WO2022247701A1 (zh) * | 2021-05-26 | 2022-12-01 | 联邦生物科技(珠海横琴)有限公司 | 多激动剂及其应用 |
CN116283997A (zh) * | 2022-09-08 | 2023-06-23 | 药康众拓(江苏)医药科技有限公司 | 氘代hgfr抑制剂药物及用途 |
CN115850179A (zh) * | 2022-12-13 | 2023-03-28 | 北京科翔中升医药科技有限公司 | 一种氘代吲唑类mapk抑制剂药物及用途 |
CN116162081A (zh) * | 2022-12-13 | 2023-05-26 | 药康众拓(江苏)医药科技有限公司 | 一类氘代吡啶酰胺类ccr6抑制剂药物及用途 |
CN116143884A (zh) * | 2023-02-03 | 2023-05-23 | 江苏师范大学 | 一类长效GLP-1/glucagon/GIP受体三重激动剂及其应用 |
Non-Patent Citations (1)
Title |
---|
"Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA";Julio Rosenstock, et al.,;《Articles》;第402卷(第10401期);第529-544页 * |
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