CN118632867A - GLP-1/GIP receptor co-agonist prodrug and its use - Google Patents
GLP-1/GIP receptor co-agonist prodrug and its use Download PDFInfo
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- CN118632867A CN118632867A CN202380017655.7A CN202380017655A CN118632867A CN 118632867 A CN118632867 A CN 118632867A CN 202380017655 A CN202380017655 A CN 202380017655A CN 118632867 A CN118632867 A CN 118632867A
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Abstract
提供了GLP‑1/GIP受体共激动剂的前药化合物,其中该GLP‑1/GIP受体共激动剂已通过二肽与该GLP‑1/GIP受体共激动剂经由酰胺键连接而被修饰。本文公开的前药具有延长的半衰期,并且在生理条件下通过由化学不稳定性驱动的非酶促反应而转化为活性GLP‑1/GIP受体共激动剂。Provided are prodrug compounds of GLP-1/GIP receptor co-agonists, wherein the GLP-1/GIP receptor co-agonist has been modified by connecting a dipeptide to the GLP-1/GIP receptor co-agonist via an amide bond. The prodrugs disclosed herein have an extended half-life and are converted to active GLP-1/GIP receptor co-agonists under physiological conditions by a non-enzymatic reaction driven by chemical instability.
Description
技术领域Technical Field
本发明涉及如下化合物的基于2,5-二酮基哌嗪(DKP)的前药及其治疗用途,所述化合物是胰高血糖素样肽1(GLP-1)受体和葡萄糖依赖性促胰岛素多肽(GIP)受体的共激动剂,所述前药具有延长的作用谱,适合口服施用于人类。The present invention relates to 2,5-diketopiperazine (DKP)-based prodrugs of the following compounds, which are co-agonists of the glucagon-like peptide 1 (GLP-1) receptor and the glucose-dependent insulinotropic polypeptide (GIP) receptor, and their therapeutic uses. The prodrugs have a prolonged spectrum of action and are suitable for oral administration to humans.
序列表的援引并入Incorporation by Reference of Sequence Listing
本申请与电子形式的序列表一起提交。该序列表的全部内容通过引用并入本文。This application is submitted with a sequence listing in electronic form. The entire contents of the sequence listing are incorporated herein by reference.
背景技术Background Art
许多治疗活性剂在口服给药后由于吸收不良或易受首过代谢影响而具有低生物利用度(例如,Salama N.N.,Fasano A.,Thakar M.,Eddington N.D.,The impact ofΔGon the oral bioavailability of low bioavailable therapeutic agents,J.Pharmacol.Exp.Ther.,2005,312,199-205)。Many therapeutically active agents have low bioavailability after oral administration due to poor absorption or susceptibility to first-pass metabolism (e.g., Salama N.N., Fasano A., Thakar M., Eddington N.D., The impact of ΔG on the oral bioavailability of low bioavailable therapeutic agents, J. Pharmacol. Exp. Ther., 2005, 312, 199-205).
前药是本身几乎无活性但可预测地转化为活性分子实体的治疗剂(例如,TestaB.,Mayer J.M,Hydrolysis in Drug and Prodrug Metabolism,Wiley-VCH,2003,第4页)。前药化学提供了精确控制在药物从给药部位清除并以高度确定的浓度在血浆中达到平衡后其作用的开始和持续时间的机会。当今临床使用的大多数前药需要酶催化才能转化为活性药物。对于在胃肠吸收后需要释放到血流中的药物,通常采用通过酶催化的前药方法。一种常见的前药方法是使用药物的酯衍生物,所述酯衍生物通过酯酶催化的水解容易地转化为活性药物(例如,Yu L.X.,Straughn A.B.,Faustion P.J.,Yang Y.,Parekh A.,Ciavarella A.B.,Asafu-Adjaye E.,Mehta M.U.,Conner D.P.,Lesko L.J.,HussainA.S.The effect of food on the relative bioavailability of rapidly dissolvingimmediate-release solid oral products containing highlysolubledrugs.Mol.Pharm.2004,1,357-362)。以酶促为主的裂解的一个缺点是患者间差异。个体之间的酶水平可能存在显著差异,导致通过酶促裂解活化前药存在生物学差异。酶水平也可能因给药部位的不同而不同。例如,众所周知,在皮下注射的情况下,身体的某些区域比其他区域产生更可预测的治疗效果。为了减少这种不可预测的效果,非酶促裂解或分子内催化特别令人感兴趣(例如,Testa B.,Mayer J.M,Hydrolysis in Drug andProdrug Metabolism,Wiley-VCH,2003,第5页)。Prodrugs are therapeutic agents that are almost inactive in themselves but predictably converted into active molecular entities (e.g., Testa B., Mayer J.M, Hydrolysis in Drug and Prodrug Metabolism, Wiley-VCH, 2003, page 4). Prodrug chemistry provides an opportunity to precisely control the onset and duration of its action after the drug is cleared from the site of administration and reaches equilibrium in the plasma at a highly determined concentration. Most prodrugs used clinically today require enzyme catalysis to be converted into active drugs. For drugs that need to be released into the bloodstream after gastrointestinal absorption, a prodrug method catalyzed by enzymes is generally used. A common prodrug method is to use an ester derivative of a drug, which is easily converted into an active drug by esterase-catalyzed hydrolysis (e.g., Yu L.X., Straughn A.B., Faustion P.J., Yang Y., Parekh A., Ciavarella A.B., Asafu-Adjaye E., Mehta M.U., Conner D.P., Lesko L.J., Hussain A.S. The effect of food on the relative bioavailability of rapidly dissolving immediate-release solid oral products containing highly soluble drugs. Mol. Pharm. 2004, 1, 357-362). One disadvantage of enzymatic cleavage is the difference between patients. There may be significant differences in enzyme levels between individuals, resulting in biological differences in the activation of prodrugs by enzymatic cleavage. Enzyme levels may also vary depending on the site of administration. For example, it is well known that in the case of subcutaneous injection, certain areas of the body produce more predictable therapeutic effects than other areas. In order to reduce such unpredictable effects, non-enzymatic cleavage or intramolecular catalysis is of particular interest (eg, Testa B., Mayer J.M, Hydrolysis in Drug and Prodrug Metabolism, Wiley-VCH, 2003, p. 5).
基于DKP的前药技术基于化学转化,其中由两个α-氨基酸组成的部分环化形成六元环,并同时释放活性药物。基于DKP的前药技术先前已有描述。例如,WO2010/071807、WO2010080605、WO2011/163012和WO 2011/162968描述了各种基于肽的前药,它们通过酰胺键与例如胰高血糖素超家族肽或其他已知药剂连接。WO2014152460和WO2016049174描述了胰高血糖素超家族肽和胰岛素的基于肽的前药,它们具有延长的半衰期。DKP-based prodrug technology is based on a chemical transformation in which a moiety consisting of two α-amino acids cyclizes to form a six-membered ring and releases the active drug simultaneously. DKP-based prodrug technology has been previously described. For example, WO2010/071807, WO2010080605, WO2011/163012 and WO 2011/162968 describe various peptide-based prodrugs that are linked to, for example, glucagon superfamily peptides or other known agents via an amide bond. WO2014152460 and WO2016049174 describe peptide-based prodrugs of glucagon superfamily peptides and insulin that have extended half-lives.
已经描述,GLP-1和GIP受体的双重激活,例如通过将GLP-1和GIP的作用组合在一种制剂中,导致一种治疗原理,与市售的GLP-1激动剂利拉鲁肽相比,其在患有2型糖尿病(T2D)和肥胖症的小鼠中具有显著更好的血糖水平降低、胰岛素分泌增加和体重减轻(例如,V AGault等人,Clin Sci(Lond),121,107-117,2011)。在人类中已经证实,天然GLP-1和GIP在共同输注后以累加的方式相互作用,与单独的GLP-1相比,具有显著增强的促胰岛素作用(M A Nauck等人,J.Clin.Endocrinol.Metab.,76,912-917,1993)。It has been described that dual activation of GLP-1 and GIP receptors, for example by combining the effects of GLP-1 and GIP in one formulation, leads to a therapeutic principle that has significantly better reductions in blood glucose levels, increased insulin secretion and weight loss in mice with type 2 diabetes (T2D) and obesity than the commercially available GLP-1 agonist liraglutide (e.g., V AGault et al., Clin Sci (Lond), 121, 107-117, 2011). It has been demonstrated in humans that natural GLP-1 and GIP interact in an additive manner after co-infusion, with significantly enhanced insulinotropic effects compared to GLP-1 alone (M A Nauck et al., J. Clin. Endocrinol. Metab., 76, 912-917, 1993).
GLP-1/GIP受体共激动剂及其潜在的医学用途在数项专利申请中有所描述,例如WO 2010/011439、WO 2013/164483、WO 2014/192284、WO 2015/067715、WO 2015/022420、WO2015/086728、WO 2015/086729、WO 2016/111971、WO 2020/023386、US 9745360、US2014/162945和US2014/0357552。例如,WO 2011/080103、WO 2012/080471、WO 2013/189988和WO2019/149880中描述了公开了GLP-1衍生物的口服递送的专利申请。GLP-1/GIP receptor co-agonists and their potential medical uses are described in several patent applications, such as WO 2010/011439, WO 2013/164483, WO 2014/192284, WO 2015/067715, WO 2015/022420, WO 2015/086728, WO 2015/086729, WO 2016/111971, WO 2020/023386, US 9745360, US 2014/162945 and US 2014/0357552. Patent applications disclosing oral delivery of GLP-1 derivatives are described, for example, in WO 2011/080103, WO 2012/080471, WO 2013/189988 and WO 2019/149880.
然而,仍然渴望对GIP和GLP-1受体具有激动剂活性且适合口服给药的化合物。希望找到对GIP和GLP-1受体均具有延长的作用持续时间的化合物,以使此类化合物的给药频率较低。因此,需要更长效的GLP-1/GIP受体共激动剂来充分发挥其在治疗诸如T2D等疾病中的潜力。However, there is still a desire for compounds that have agonist activity at both GIP and GLP-1 receptors and are suitable for oral administration. It is desirable to find compounds that have a prolonged duration of action at both GIP and GLP-1 receptors so that such compounds can be administered less frequently. Therefore, longer-acting GLP-1/GIP receptor co-agonists are needed to fully realize their potential in treating diseases such as T2D.
发明内容Summary of the invention
基于肽的药物是高效药物,但作用持续时间相对较短,且治疗指数多变。可以采用前药技术以使其适合于特定给药方案(例如每周一次给药)的方式优化药物的性质。前药通过酶促或非酶促化学过程进行转化,导致生物活性药物分子(在本文中称为活性药物)在体内的缓慢释放。Peptide-based drugs are highly effective drugs, but the duration of action is relatively short and the therapeutic index is variable. Prodrug technology can be used to optimize the properties of the drug in a way that makes it suitable for a specific dosing regimen (e.g., once-weekly dosing). Prodrugs are converted by enzymatic or non-enzymatic chemical processes, resulting in the slow release of biologically active drug molecules (referred to herein as active drugs) in the body.
本公开涉及具有理想的性质,例如用于每周一次口服给药的GLP-1/GIP受体共激动剂前药。本文描述的前药被设计用于延迟作用的开始并延长活性药物(即GLP-1/GIP受体共激动剂)的半衰期。延迟作用的开始是有利的,因为这允许前药在活化之前的全身分布。因此,前药的给药可消除给药时由峰值活性引起的并发症并增加活性药物的治疗指数。与活性药物相比,完整的前药不会在显著程度上发挥生物活性。一旦在前药转化时释放出活性药物,即由活性药物产生生物活性。与释放的活性药物相比,前药的生物活性降低是有利的,因为这允许施用相对大量的前药,而没有伴随的副作用和给药过量的风险。The present disclosure relates to GLP-1/GIP receptor co-agonist prodrugs having desirable properties, such as for once-weekly oral administration. The prodrugs described herein are designed to delay the onset of action and extend the half-life of the active drug (i.e., the GLP-1/GIP receptor co-agonist). Delaying the onset of action is advantageous because it allows systemic distribution of the prodrug prior to activation. Therefore, administration of the prodrug can eliminate complications caused by peak activity during administration and increase the therapeutic index of the active drug. The complete prodrug does not exert biological activity to a significant extent compared to the active drug. Once the active drug is released during prodrug conversion, biological activity is generated by the active drug. The reduced biological activity of the prodrug compared to the released active drug is advantageous because it allows the administration of relatively large amounts of the prodrug without the risk of accompanying side effects and overdose.
本发明涉及GLP-1/GIP受体共激动剂前药。另外,或备选地,本发明涉及具有延长的体内终末半衰期的GLP-1/GIP受体共激动剂前药。The present invention relates to GLP-1/GIP receptor co-agonist prodrugs. Additionally, or alternatively, the present invention relates to GLP-1/GIP receptor co-agonist prodrugs having a prolonged terminal half-life in vivo.
在第一方面,本发明涉及作为GLP-1/GIP受体共激动剂的前药的化合物。在一些实施方案中,该化合物包含式I:B-Z,其中Z为GLP-1/GIP受体共激动剂(活性药物),B为二肽(“二肽B”),并且其中该GLP-1/GIP受体共激动剂的N端氨基通过肽键与B连接。在一些实施方案中,所述二肽B包含共价连接的部分,例如能够与哺乳动物血浆蛋白如哺乳动物血清白蛋白形成非共价结合相互作用的取代基。在一些实施方案中,所述二肽B能够通过分子内反应从活性药物Z上裂解下来,从而释放活性药物(即GLP-1/GIP受体共激动剂)并形成2,5-二酮基哌嗪(DKP)作为副产物。在一些实施方案中,该分子内反应在生理条件下发生。另外,或备选地,在一些实施方案中,该分子内反应在没有酶活性的情况下发生。In a first aspect, the present invention relates to compounds that are prodrugs of GLP-1/GIP receptor co-agonists. In some embodiments, the compound comprises formula I: B-Z, wherein Z is a GLP-1/GIP receptor co-agonist (active drug), B is a dipeptide ("dipeptide B"), and wherein the N-terminal amino group of the GLP-1/GIP receptor co-agonist is linked to B via a peptide bond. In some embodiments, the dipeptide B comprises a covalently linked portion, such as a substituent capable of forming a non-covalent binding interaction with a mammalian plasma protein such as mammalian serum albumin. In some embodiments, the dipeptide B can be cleaved from the active drug Z by an intramolecular reaction, thereby releasing the active drug (i.e., the GLP-1/GIP receptor co-agonist) and forming 2,5-diketopiperazine (DKP) as a byproduct. In some embodiments, the intramolecular reaction occurs under physiological conditions. Additionally, or alternatively, in some embodiments, the intramolecular reaction occurs in the absence of enzymatic activity.
在第二方面,本发明涉及包含如本文所述化合物的药物组合物。In a second aspect, the invention relates to a pharmaceutical composition comprising a compound as described herein.
在第三方面,本发明涉及如本文所述的化合物或包含本文所述化合物的药物组合物,其用作药物。In a third aspect, the present invention relates to a compound as described herein or a pharmaceutical composition comprising a compound as described herein for use as a medicament.
在一个功能方面,本发明提供了具有适合每周一次给药的转化半衰期的前药(例如,如本文所述的化合物)。另外,或备选地,在另一个功能方面,本发明提供了具有适合每周一次给药的观察到的终末半衰期的前药。另外,或备选地,在另一个功能方面,本发明提供了具有高得惊人的口服生物利用度的前药。In one functional aspect, the invention provides prodrugs (e.g., compounds as described herein) having conversion half-lives suitable for once-weekly dosing. Additionally, or alternatively, in another functional aspect, the invention provides prodrugs having observed terminal half-lives suitable for once-weekly dosing. Additionally, or alternatively, in another functional aspect, the invention provides prodrugs having surprisingly high oral bioavailability.
本发明的另一方面涉及本文所述化合物的医药用途。另外,或备选地,本发明涉及本文所述化合物用于预防和/或治疗2型糖尿病的用途。另外,或备选地,本发明涉及本文所述化合物用于预防和/或治疗肥胖症的用途。另外,或备选地,本发明涉及本文所述化合物用于预防和/或治疗肝脏疾病的用途。Another aspect of the present invention relates to the medical use of the compounds described herein. Additionally, or alternatively, the present invention relates to the use of the compounds described herein for preventing and/or treating type 2 diabetes. Additionally, or alternatively, the present invention relates to the use of the compounds described herein for preventing and/or treating obesity. Additionally, or alternatively, the present invention relates to the use of the compounds described herein for preventing and/or treating liver disease.
本发明的另一方面涉及通过向有需要的患者施用本文所述化合物来治疗疾病的方法。在一些实施方案中,该疾病是2型糖尿病。在一些实施方案中,该疾病是超重。在一些实施方案中,该疾病是肥胖症。Another aspect of the present invention relates to a method of treating a disease by administering a compound described herein to a patient in need thereof. In some embodiments, the disease is type 2 diabetes. In some embodiments, the disease is overweight. In some embodiments, the disease is obesity.
本发明还可以解决从示例性实施方案的公开内容中将会明显看出的其他问题。The present invention may also solve other problems that will be apparent from the disclosure of the exemplary embodiments.
具体实施方式DETAILED DESCRIPTION
在下文中,希腊字母可用其符号或相应的书面名称表示,例如:α=alpha;β=beta;ε=epsilon;γ=gamma;ω=omega;等等。此外,希腊字母μ也可用“u”表示,例如μl=ul或μM=uM。化学图中的符号表示与相邻部分的连接点。在下文中,除非在说明书中另有说明,否则以单数形式呈现的术语也包括复数情况,例如,当提及“化合物”时,应理解这包括落入所述化合物的宽泛定义内的所有单个变体。如本文所用的,一”表示“一个(种)或多个(种)”。本发明涉及作为GLP-1/GIP受体共激动剂的前药的化合物,例如具有理想的性质,例如用于每周一次口服给药的GLP-1/GIP受体共激动剂的前药。这些化合物在生理条件下以受控方式转化为活性GLP-1/GIP受体共激动剂(活性药物)。In the following text, Greek letters may be represented by their symbols or the corresponding written names, for example: α = alpha; β = beta; ε = epsilon; γ = gamma; ω = omega; etc. In addition, the Greek letter μ can also be represented by "u", for example μl = ul or μM = uM. Symbols in chemical diagrams Indicates the point of connection with the adjacent part. In the following, unless otherwise stated in the specification, terms presented in the singular also include plural cases, for example, when referring to a "compound", it should be understood that this includes all individual variants falling within the broad definition of the compound. As used herein, "one" means "one (kind) or more (kinds)". The present invention relates to compounds that are prodrugs of GLP-1/GIP receptor co-agonists, for example, prodrugs of GLP-1/GIP receptor co-agonists having ideal properties, such as for once-weekly oral administration. These compounds are converted into active GLP-1/GIP receptor co-agonists (active drugs) in a controlled manner under physiological conditions.
在第一方面,本发明涉及作为GLP-1/GIP受体共激动剂的前药的化合物,所述化合物包含式I:B-Z,其中Z为GLP-1/GIP受体共激动剂(活性药物),其在前药转化时从B上释放下来。在第二方面,本发明涉及包含本文所述化合物的药物组合物。本发明的另一方面涉及本文所述化合物的医药用途。另外,或备选地本发明涉及本文所述化合物用于预防和/或治疗2型糖尿病的用途。另外,或备选地,本发明涉及本文所述化合物用于预防和/或治疗肥胖症的用途。另外,或备选地,本发明涉及本文所述化合物用于预防和/或治疗肝脏疾病的用途。In a first aspect, the present invention relates to a compound that is a prodrug of a GLP-1/GIP receptor co-agonist, the compound comprising formula I: B-Z, wherein Z is a GLP-1/GIP receptor co-agonist (active drug) that is released from B upon prodrug conversion. In a second aspect, the present invention relates to a pharmaceutical composition comprising the compound described herein. Another aspect of the present invention relates to the medical use of the compound described herein. Additionally or alternatively, the present invention relates to the use of the compound described herein for preventing and/or treating type 2 diabetes. Additionally or alternatively, the present invention relates to the use of the compound described herein for preventing and/or treating obesity. Additionally or alternatively, the present invention relates to the use of the compound described herein for preventing and/or treating liver disease.
一般定义General Definition
术语“化合物”涉及GLP-1/GIP受体共激动剂的前药。本发明的化合物可被称为“化合物”,而术语“化合物”还旨在涵盖其药学上相关的形式,即,其药学上可接受的盐、酰胺或酯。The term "compound" relates to a prodrug of a GLP-1/GIP receptor co-agonist. The compounds of the present invention may be referred to as "compounds", whereas the term "compound" is also intended to encompass pharmaceutically relevant forms thereof, ie, pharmaceutically acceptable salts, amides or esters thereof.
如本文所用的术语“多肽”或“多肽序列”是指一系列通过酰胺键(例如肽键)互相连接的两个或更多个氨基酸。术语多肽可与术语“肽”和术语“蛋白质”互换使用。As used herein, the term "polypeptide" or "polypeptide sequence" refers to a series of two or more amino acids linked to each other by amide bonds (eg, peptide bonds). The term polypeptide can be used interchangeably with the term "peptide" and the term "protein".
术语“衍生物”通常是指化学修饰的多肽(例如,GLP-1/GIP受体共激动剂)或二肽,其中一个或多个取代基与该多肽或二肽的氨基酸序列共价连接,例如通过连接到Lys的ε-氨基的键来连接。在一些实施方案中,本发明的化合物包含衍生物(例如,GLP-1/GIP受体共激动剂的衍生物和/或二肽的衍生物),该衍生物已被修饰,使得一个或多个具有延长性质的取代基共价连接至该多肽或二肽的氨基酸序列。The term "derivative" generally refers to a chemically modified polypeptide (e.g., a GLP-1/GIP receptor co-agonist) or dipeptide in which one or more substituents are covalently linked to the amino acid sequence of the polypeptide or dipeptide, for example, via a bond to the ε-amino group of Lys. In some embodiments, the compounds of the invention include derivatives (e.g., derivatives of GLP-1/GIP receptor co-agonists and/or derivatives of dipeptides) that have been modified such that one or more substituents having an extended nature are covalently linked to the amino acid sequence of the polypeptide or dipeptide.
术语“二肽衍生物”意指该二肽被化学修饰,使得其带有至少一个取代基(例如,取代基b,如本文所述)。在一些实施方案中,可带有两个或更多个取代基。The term "dipeptide derivative" means that the dipeptide is chemically modified so that it carries at least one substituent (eg, substituent b, as described herein). In some embodiments, it may carry two or more substituents.
术语“GLP-1/GIP受体共激动剂衍生物”是指经化学修饰而使其带有取代基的GLP-1/GIP受体共激动剂。例如,这样的GLP-1/GIP受体共激动剂衍生物可包含一个或多个取代基,该取代基与该多肽的氨基酸序列共价连接,例如通过连接到Lys的ε-氨基的键来连接。The term "GLP-1/GIP receptor co-agonist derivative" refers to a GLP-1/GIP receptor co-agonist that has been chemically modified to carry a substituent. For example, such a GLP-1/GIP receptor co-agonist derivative may include one or more substituents that are covalently linked to the amino acid sequence of the polypeptide, such as through a bond to the ε-amino group of Lys.
术语“与脂肪酸缀合的氨基酸”是指具有官能团的任何蛋白型(proteinogenic)或非蛋白型(non-proteinogenic)氨基酸,该官能团已被化学修饰以通过与脂肪酸的共价键或优选地通过连接体与该脂肪酸缀合。此类官能团的实例包括氨基(例如Lys)、巯基(例如Cys)和羧基(例如Glu或Asp)。在一些实施方案中,该缀合的氨基酸是Lys。当将脂肪酸与所述具有官能团的蛋白型或非蛋白型氨基酸缀合时,可以使用脂肪酸前体,如二羧酸(例如CO2H-(CH2)-CO2H,其中n=10-22)。The term "amino acid conjugated to a fatty acid" refers to any proteinogenic or non-proteinogenic amino acid having a functional group that has been chemically modified to be conjugated to the fatty acid through a covalent bond to the fatty acid or, preferably, through a linker. Examples of such functional groups include amino groups (e.g., Lys), sulfhydryl groups (e.g., Cys), and carboxyl groups (e.g., Glu or Asp). In some embodiments, the conjugated amino acid is Lys. When conjugating a fatty acid to the proteinogenic or non-proteinogenic amino acid having a functional group, a fatty acid precursor such as a dicarboxylic acid (e.g., CO 2 H—(CH 2 )—CO 2 H, wherein n=10-22) can be used.
术语“脂肪酸”是指具有脂肪族或环状烃链的任选取代的羧酸,其中该脂肪族链是饱和的或不饱和的。在一些实施方案中,该脂肪酸是C12-C24饱和羧酸,如C16-C22饱和羧酸。在一些实施方案中,该脂肪酸包含额外的官能团。The term "fatty acid" refers to an optionally substituted carboxylic acid having an aliphatic or cyclic hydrocarbon chain, wherein the aliphatic chain is saturated or unsaturated. In some embodiments, the fatty acid is a C 12 -C 24 saturated carboxylic acid, such as a C 16 -C 22 saturated carboxylic acid. In some embodiments, the fatty acid comprises additional functional groups.
如本文所用的术语“亲脂性部分”是指包含脂肪族和/或环状烃部分的部分,其总共有多于6个且少于30个碳原子,优选多于8个且少于20个碳原子。在一些实施方案中,亲脂性部分包含含有至少8个连续-CH2-基团的碳链。在一些实施方案中,亲脂性部分包含至少10个连续-CH2-基团,如至少12个连续-CH2-基团、至少14个连续-CH2-基团、至少16个连续的-CH2-基团或至少18个连续-CH2-基团。在一些实施方案中,亲脂性部分可包含6至30个之间的任意数目的连续-CH2-基团(例如6、7、8、9个等)。As used herein, the term "lipophilic moiety" refers to a moiety comprising an aliphatic and/or cyclic hydrocarbon portion having a total of more than 6 and less than 30 carbon atoms, preferably more than 8 and less than 20 carbon atoms. In some embodiments, the lipophilic moiety comprises a carbon chain comprising at least 8 consecutive -CH 2 - groups. In some embodiments, the lipophilic moiety comprises at least 10 consecutive -CH 2 - groups, such as at least 12 consecutive -CH 2 - groups, at least 14 consecutive -CH 2 - groups, at least 16 consecutive -CH 2 - groups, or at least 18 consecutive -CH 2 - groups. In some embodiments, the lipophilic moiety may comprise any number of consecutive -CH 2 - groups between 6 and 30 (e.g., 6, 7, 8, 9, etc.).
如本文在亲脂性部分的语境中使用的术语“远端羧酸”是指相对于亲脂性部分与相邻部分的连接点,连接至亲脂性部分的最远(末端)点的羧酸,例如在本文所述的化合物中,具有远端羧酸的亲脂性部分(例如化学式1)是延长部分,并且相对于亲脂性部分与相邻连接体元件(例如化学式2、化学式3、化学式4或化学式5)的连接点,羧酸连接至亲脂性部分的最远(末端)点。具有远端羧酸的亲脂性部分的非限制性实例是化学式1。The term "distal carboxylic acid" as used herein in the context of a lipophilic moiety refers to a carboxylic acid that is attached to the most distal (terminal) point of the lipophilic moiety relative to the point of attachment of the lipophilic moiety to an adjacent moiety, for example, in the compounds described herein, the lipophilic moiety with a distal carboxylic acid (e.g., Formula 1) is an extended moiety, and the carboxylic acid is attached to the most distal (terminal) point of the lipophilic moiety relative to the point of attachment of the lipophilic moiety to an adjacent linker element (e.g., Formula 2, Formula 3, Formula 4, or Formula 5). A non-limiting example of a lipophilic moiety with a distal carboxylic acid is Formula 1.
术语“治疗指数”描述药物变成毒性时的血药浓度与药物有效时的血药浓度之间的比率。治疗指数(TI)越大,药物越安全。如果TI很小(两种浓度之差非常小),则必须谨慎地给予药物,并应密切监测接受药物的人是否出现任何药物毒性迹象。The term "therapeutic index" describes the ratio between the blood concentration at which a drug becomes toxic and the blood concentration at which the drug is effective. The larger the therapeutic index (TI), the safer the drug. If the TI is small (the difference between the two concentrations is very small), the drug must be given with caution, and the person receiving the drug should be closely monitored for any signs of drug toxicity.
氨基酸Amino Acids
如本文所用的术语“氨基酸”是指任何氨基酸,即蛋白型氨基酸和非蛋白型氨基酸两者。如本文所用的术语“蛋白型氨基酸”是指由人类遗传密码编码的20种标准氨基酸。如本文所用的术语“非蛋白型氨基酸”是指不符合蛋白型氨基酸资格的任何氨基酸。非蛋白型氨基酸或者不存在于蛋白质中,或者不通过标准细胞机制产生(例如,它们可能已经经历翻译后修饰)。非蛋白型氨基酸的非限制性实例是Aib(α-氨基异丁酸或2-氨基异丁酸)、正亮氨酸、正缬氨酸以及蛋白型氨基酸的D-异构体。As used herein, the term "amino acid" refers to any amino acid, i.e., both proteinogenic amino acids and non-proteinogenic amino acids. As used herein, the term "proteinogenic amino acids" refers to the 20 standard amino acids encoded by the human genetic code. As used herein, the term "non-proteinogenic amino acids" refers to any amino acid that does not meet the qualifications of proteinogenic amino acids. Non-proteinogenic amino acids are either not present in proteins, or are not produced by standard cellular mechanisms (e.g., they may have undergone post-translational modifications). Non-limiting examples of non-proteinogenic amino acids are Aib (α-aminoisobutyric acid or 2-aminoisobutyric acid), norleucine, norvaline, and the D-isomers of proteinogenic amino acids.
通常,如本文所用的氨基酸残基(例如,在多肽序列的语境中)可用其全名、其单字母代码和/或其三字母代码来表示。这三种方式完全等效并且可互换使用。在下文中,未说明其光学异构体的本文所述肽的各个氨基酸都应被理解为意指L-异构体(除非另有说明)。可以并入本发明化合物中的非蛋白型氨基酸的实例在表1中列出。Generally, as used herein, amino acid residues (e.g., in the context of a polypeptide sequence) may be represented by their full name, their one-letter code, and/or their three-letter code. These three methods are fully equivalent and may be used interchangeably. Hereinafter, each amino acid of the peptides described herein for which the optical isomers thereof are not specified shall be understood to mean the L-isomer (unless otherwise specified). Examples of non-proteinogenic amino acids that may be incorporated into the compounds of the invention are listed in Table 1.
表1.可以并入本发明化合物中的非蛋白型氨基酸的非限制性实例。Table 1. Non-limiting examples of non-proteinogenic amino acids that can be incorporated into compounds of the invention.
前药Prodrug
如本文所用的术语“前药”是指在体内通过酶促或非酶促化学过程经历化学转化从而导致活性药物释放的化合物。如本文所用的术语“活性药物”是指在前药转化时从前药释放出来的药理活性化合物。活性药物的非限制性实例是如本文所述的母体化合物1-5。如本文在前药的语境中使用的术语“转化”是指其中前药以酶促或非酶促方式转化从而导致活性药物释放的过程。转化发生的速率可以通过“转化半衰期”来量化。“转化半衰期”是前药浓度因转化而减半所需的时间长度。“转化半衰期”还可被称为“前药到药物的转化半衰期”或“前药到活性药物的转化半衰期”。The term "prodrug" as used herein refers to a compound that undergoes chemical transformation in vivo by an enzymatic or non-enzymatic chemical process, thereby causing the release of an active drug. The term "active drug" as used herein refers to a pharmacologically active compound released from a prodrug when the prodrug is transformed. A non-limiting example of an active drug is a parent compound 1-5 as described herein. The term "conversion" as used herein in the context of a prodrug refers to a process in which a prodrug is converted enzymatically or non-enzymatically, thereby causing the release of an active drug. The rate at which the conversion occurs can be quantified by a "conversion half-life". "Conversion half-life" is the length of time required for the prodrug concentration to be halved due to the conversion. "Conversion half-life" may also be referred to as "conversion half-life of prodrug to drug" or "conversion half-life of prodrug to active drug".
前药不会在显著程度上发挥预期的药理活性,例如,它不会在使其与预期治疗方案不相容的程度上发挥预期的药理活性。一旦释放出活性药物,就从活性药物产生与前药的预期治疗相关的药理活性。当活性药物从前药中释放出来时,它被称为“游离形式”。前药可以在基于二肽的末端酰胺延伸部的分子内环化后实现所需的转化,该延伸部随之从活性药物上切下,导致释放出游离形式的活性药物。这样的分子内环化可以在生理条件下作为非依赖于酶的过程发生,例如通过2,5-二酮基哌嗪(DKP)的形成。在通过所述分子内环化形成DKP而转化为活性药物的前药中,在转化时释放出活性药物的部分被称为“DKP部分”。“DKP部分”包含二肽部分(例如,二肽或二肽衍生物)。在一些实施方案中,前药可以在DKP部分的二肽部分与活性药物的脂肪族胺基团之间具有暂时的酰胺键,如肽键。在一些实施方案中,DKP部分通过GLP-1/GIP受体共激动剂骨架的位置1处的氨基酸的α-氨基,即在DKP部分的羧酸基团与GLP-1/GIP受体共激动剂骨架的位置1处的Tyr的α-氨基之间形成的酰胺键,与GLP-1/GIP受体共激动剂连接。在一些实施方案中,DKP部分通过酰化,即通过在DKP部分的羧酸基团与GLP-1/GIP受体共激动剂骨架中Tyr的α-氨基之间形成的酰胺键,与GLP-1/GIP受体共激动剂骨架中Tyr1的氨基连接。The prodrug will not exert the expected pharmacological activity to a significant extent, for example, it will not exert the expected pharmacological activity to the extent that it is incompatible with the expected treatment regimen. Once the active drug is released, the pharmacological activity related to the expected treatment of the prodrug is generated from the active drug. When the active drug is released from the prodrug, it is referred to as the "free form". The prodrug can achieve the desired conversion after the intramolecular cyclization of the terminal amide extension based on the dipeptide, and the extension is then cut off from the active drug, resulting in the release of the active drug in free form. Such intramolecular cyclization can occur as an enzyme-independent process under physiological conditions, such as through the formation of 2,5-diketopiperazine (DKP). In the prodrug that is converted into an active drug by forming DKP through the intramolecular cyclization, the part that releases the active drug during the conversion is referred to as the "DKP part". The "DKP part" includes a dipeptide part (e.g., a dipeptide or a dipeptide derivative). In some embodiments, the prodrug may have a temporary amide bond, such as a peptide bond, between the dipeptide part of the DKP part and the aliphatic amine group of the active drug. In some embodiments, the DKP moiety is linked to the GLP-1/GIP receptor co-agonist via an α-amino group of the amino acid at position 1 of the GLP-1/GIP receptor co-agonist backbone, i.e., an amide bond formed between the carboxylic acid group of the DKP moiety and the α-amino group of Tyr at position 1 of the GLP-1/GIP receptor co-agonist backbone. In some embodiments, the DKP moiety is linked to the amino group of Tyr1 in the GLP-1/GIP receptor co-agonist backbone by acylation, i.e., an amide bond formed between the carboxylic acid group of the DKP moiety and the α-amino group of Tyr in the GLP-1/GIP receptor co-agonist backbone.
转化半衰期可能受DKP部分的结构性质的影响。例如,可通过使用本申请中举例说明的二肽B来获得理想的转化半衰期。转化半衰期可能受DKP部分所连接的活性药物的氨基酸的结构性质的影响。在一些实施方案中,可通过使用本申请中举例说明的活性药物的N端氨基酸残基获得理想的转化半衰期。在一些实施方案中,DKP部分是与活性药物连接的基于二肽的延伸部。在一些实施方案中,DKP部分包含另外的结构元件,例如与二肽共价连接的取代基(本文中也称为“二肽衍生物”)。在前药转化和活性药物释放后,DKP作为副产物形成。DKP可以是无活性的或者可以与药理活性相关。在一些实施方案中,本文所述的前药的转化主要以非酶促方式发生。在一些实施方案中,本文所述的前药的转化仅以非酶促方式发生。The conversion half-life may be affected by the structural properties of the DKP part. For example, the ideal conversion half-life can be obtained by using the dipeptide B illustrated in the present application. The conversion half-life may be affected by the structural properties of the amino acids of the active drug to which the DKP part is connected. In some embodiments, the ideal conversion half-life can be obtained by using the N-terminal amino acid residue of the active drug illustrated in the present application. In some embodiments, the DKP part is a dipeptide-based extension connected to the active drug. In some embodiments, the DKP part comprises additional structural elements, such as substituents covalently linked to the dipeptide (also referred to herein as "dipeptide derivatives"). After the prodrug is converted and the active drug is released, DKP is formed as a by-product. DKP may be inactive or may be associated with pharmacological activity. In some embodiments, the conversion of the prodrug described herein occurs mainly in a non-enzymatic manner. In some embodiments, the conversion of the prodrug described herein occurs only in a non-enzymatic manner.
在一些实施方案中,本文所述的化合物是前药或其药学上可接受的盐、酯或酰胺。在一些实施方案中,该前药是根据式I的化合物,其中B为任选地包含取代基b的二肽,其中取代基b包含延长体和可选的连接体,或由延长体和可选的连接体组成。在一些实施方案中,Z为带有取代基z的GLP-1/GIP受体共激动剂;并且其中该GLP-1/GIP受体共激动剂的N端氨基通过肽键与B连接。在本发明的一些实施方案中,B为DKP部分。In some embodiments, the compounds described herein are prodrugs or pharmaceutically acceptable salts, esters or amides thereof. In some embodiments, the prodrug is a compound according to formula I, wherein B is a dipeptide optionally comprising a substituent b, wherein the substituent b comprises an extension and an optional linker, or consists of an extension and an optional linker. In some embodiments, Z is a GLP-1/GIP receptor co-agonist with a substituent z; and wherein the N-terminal amino group of the GLP-1/GIP receptor co-agonist is connected to B via a peptide bond. In some embodiments of the present invention, B is a DKP moiety.
在一些实施方案中,本文所述的化合物包含DKP部分。在一些实施方案中,本文所述的化合物包含含有DKP部分和活性药物的前药。在一些实施方案中,该活性药物是GLP-1/GIP受体共激动剂(例如,活性药物Z)。在一些实施方案中,DKP部分包含二肽(例如,二肽B),该二肽任选地带有一个或多个取代基。In some embodiments, the compounds described herein include a DKP portion. In some embodiments, the compounds described herein include a prodrug containing a DKP portion and an active drug. In some embodiments, the active drug is a GLP-1/GIP receptor co-agonist (e.g., active drug Z). In some embodiments, the DKP portion includes a dipeptide (e.g., dipeptide B), which optionally carries one or more substituents.
以下提供了对本文所述化合物使用的命名法的示例,所述化合物在本文中也被称为“前药”,包含DKP部分和作为活性药物的GLP-1/GIP受体共激动剂:K[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]-GAPPPS-OH。在该化合物中,DKP部分包含通过酰胺键互相连接的Lys残基和Sar残基。(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基部分通过酰胺键与二肽的Lys残基的ε-氮原子共价连接,而2-[2-[2-[[2-[2-[2-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基部分通过酰胺键与GLP-1/GIP受体共激动剂的Lys残基的ε-氮原子共价连接。Sar残基的羧基通过酰胺键与GLP-1/GIP受体共激动剂的氨基酸序列的N端氨基共价连接。该化合物的完整结构如下所示:The following provides an example of the nomenclature used for compounds described herein, which are also referred to herein as "prodrugs" comprising a DKP moiety and a GLP-1/GIP receptor co-agonist as an active drug: K[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butanoyl]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-GAPPPS-OH. In this compound, the DKP moiety comprises a Lys residue and a Sar residue interconnected by an amide bond. The (4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl moiety is covalently linked to the ε-nitrogen atom of the Lys residue of the dipeptide via an amide bond, while the 2-[2-[2-[[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl moiety is covalently linked to the ε-nitrogen atom of the Lys residue of the GLP-1/GIP receptor co-agonist via an amide bond. The carboxyl group of the Sar residue is covalently linked to the N-terminal amino group of the amino acid sequence of the GLP-1/GIP receptor co-agonist via an amide bond. The complete structure of the compound is shown below:
取代基Substituents
如本文所用的术语“取代基”是指与二肽或多肽(例如,GLP-1/GIP受体共激动剂)的氨基酸共价连接的部分。在一些实施方案中,取代基z通过Lys与GLP-1/GIP受体共激动剂连接。在一些实施方案中,取代基b与GLP-1/GIP受体共激动剂的DKP部分(例如,本发明化合物中存在的二肽部分(例如,二肽B))的氨基酸残基连接,从而形成DKP部分的一部分。如果取代基与多肽或二肽连接,则该多肽或二肽被称为“取代的”。当取代基与多肽或氨基酸残基共价连接时,所述多肽或氨基酸被称为“带有”取代基。取代基可包含一系列单独定义的部分;这些部分可被称为“取代基元件”。“取代基元件”的非限制性实例是“延长体”和“连接体”。The term "substituent" as used herein refers to a moiety covalently linked to an amino acid of a dipeptide or polypeptide (e.g., a GLP-1 / GIP receptor co-agonist). In some embodiments, the substituent z is linked to the GLP-1 / GIP receptor co-agonist via Lys. In some embodiments, the substituent b is linked to an amino acid residue of the DKP portion of the GLP-1 / GIP receptor co-agonist (e.g., a dipeptide portion (e.g., dipeptide B) present in the compounds of the invention), thereby forming a portion of the DKP portion. If a substituent is linked to a polypeptide or dipeptide, the polypeptide or dipeptide is referred to as "substituted". When a substituent is covalently linked to a polypeptide or amino acid residue, the polypeptide or amino acid is referred to as "carrying" a substituent. A substituent may contain a series of separately defined moieties; these moieties may be referred to as "substituent elements". Non-limiting examples of "substituent elements" are "extensions" and "connectors".
取代基可能能够与白蛋白形成非共价结合相互作用,从而促进化合物在血流中的循环,从而具有延长化合物在血流中的存在时间的作用,因为带有取代基的化合物和白蛋白的聚集体仅缓慢崩解以释放该化合物的游离形式;因此,该取代基作为一个整体也可被称为“白蛋白结合部分”,并且该取代基可被称为具有“延长作用”。取代基可包含尤其与白蛋白结合相关,从而与作用延长相关的部分,该部分可被称为“延长体”或“延长部分”。术语“延长体”和“延长部分”在本文中可互换使用。“延长体”可以是亲脂性部分(例如脂肪酸)。“延长体”可以是脂肪酸(例如C16-C22羧酸)。表2中显示了“延长体”的非限制性实例。在化学式1中,用来描述通过共价键与连接体或多肽的连接点。The substituent may be able to form a non-covalent binding interaction with albumin, thereby promoting the circulation of the compound in the bloodstream, thereby having the effect of prolonging the presence time of the compound in the bloodstream, because the aggregate of the compound with the substituent and albumin only slowly disintegrates to release the free form of the compound; therefore, the substituent as a whole may also be referred to as an "albumin binding portion", and the substituent may be referred to as having a "prolonging effect". The substituent may include a portion that is particularly associated with albumin binding and, thereby, with prolonging the effect, which portion may be referred to as an "prolonger" or "prolonger portion". The terms "prolonger" and "prolonger portion" are used interchangeably herein. An "prolonger" may be a lipophilic portion (e.g., a fatty acid). An "prolonger" may be a fatty acid (e.g., a C 16 -C 22 carboxylic acid). Non-limiting examples of "prolongers" are shown in Table 2. In Formula 1, Used to describe the point of attachment to a linker or peptide via a covalent bond.
表2:“延长体”的非限制性实例。Table 2: Non-limiting examples of "elongated bodies".
取代基可包含位于延长部分与同多肽的氨基酸残基的连接点之间的部分,该部分可被称为“连接体”。连接体可包含数个“连接体元件”。可以选择连接体元件以使得它们改善分子的整体性质,例如,使得它们改善口服生物利用度、转化半衰期或延长作用,从而改善化合物口服给药后的总体暴露概况。Substituents may include a portion located between the point of attachment of the prolonging moiety to the amino acid residue of the same polypeptide, which portion may be referred to as a "linker". A linker may include several "linker elements". Linker elements may be selected so that they improve the overall properties of the molecule, for example, so that they improve oral bioavailability, conversion half-life or prolongation of action, thereby improving the overall exposure profile of the compound after oral administration.
表3中列出了连接体元件的非限制性实例。在化学式2-5中,用来描述与延长体或多肽的连接点。Non-limiting examples of linker elements are listed in Table 3. In Formulas 2-5, Used to describe the point of attachment to an extension or polypeptide.
表3.连接体元件的非限制性实例Table 3. Non-limiting examples of connector elements
在一些实施方案中,取代基为L-P(式III),其中P包含具有远端羧酸的亲脂性部分或由具有远端羧酸的亲脂性部分组成,并且P具有延长性质。在一些实施方案中,P为化学式1。在一些实施方案中,P为化学式1且L为包含连接体元件A1-A5的连接体:In some embodiments, the substituent is LP (Formula III), wherein P comprises or consists of a lipophilic moiety having a distal carboxylic acid, and P is of an extended nature. In some embodiments, P is Formula 1. In some embodiments, P is Formula 1 and L is a linker comprising linker elements A 1 -A 5 :
L-P(式III),L-P (Formula III),
其中P为化学式1,并且其中L为式IV:wherein P is of Formula 1, and wherein L is of Formula IV:
A1-A2-A3-A4-A5(式IV),A 1 -A 2 -A 3 -A 4 -A 5 (Formula IV),
其中A1与二肽或GLP-1/GIP受体共激动剂的氨基酸共价结合,并且选自化学式2、化学式3、化学式4和化学式5;其中A5与P共价结合并且是化学式2;其中A2、A3和A4各自单独地选自化学式2、化学式3、化学式4和化学式5,或者不存在,条件是如果A2、A3、A4和A5不存在,则A1也与P共价结合。wherein A1 is covalently bound to an amino acid of a dipeptide or a GLP-1/GIP receptor co-agonist and is selected from Formula 2, Formula 3, Formula 4 and Formula 5; wherein A5 is covalently bound to P and is Formula 2; wherein A2 , A3 and A4 are each individually selected from Formula 2, Formula 3, Formula 4 and Formula 5, or are absent, provided that if A2 , A3 , A4 and A5 are absent, then A1 is also covalently bound to P.
表4中列出了包含亲脂性部分的取代基的非限制性实例。在一些实施方案中,该取代基选自表4。Non-limiting examples of substituents comprising a lipophilic moiety are listed in Table 4. In some embodiments, the substituent is selected from Table 4.
表4.取代基的非限制性实例。Table 4. Non-limiting examples of substituents.
如果取代基附接至本文所述化合物的二肽部分(例如二肽B),则该取代基在本文中被称为“取代基b”。在一些实施方案中,取代基b包含根据化学式1的延长体,其中n为14、16或18;以及任选地连接体,其中该连接体包含一个或多个γGlu(化学式2)和/或一个或多个Ado(化学式3)和/或一个或多个Gly(化学式4)和/或一个或多个εLys(化学式5)。在一些实施方案中,取代基b选自化学式16、化学式17、化学式18、化学式19、化学式20、化学式21和化学式22。If a substituent is attached to a dipeptide portion of a compound described herein (e.g., dipeptide B), the substituent is referred to herein as "substituent b". In some embodiments, substituent b comprises an extension according to Formula 1, wherein n is 14, 16, or 18; and optionally a linker, wherein the linker comprises one or more γGlu (Formula 2) and/or one or more Ado (Formula 3) and/or one or more Gly (Formula 4) and/or one or more εLys (Formula 5). In some embodiments, substituent b is selected from Formula 16, Formula 17, Formula 18, Formula 19, Formula 20, Formula 21, and Formula 22.
如果取代基附接至本文所述化合物的GLP-1/GIP受体共激动剂(例如活性药物Z),则该取代基在本文中被称为“取代基z”。在一些实施方案中,取代基z包含根据化学式1的延长体(其中n为14、16或18)和连接体,或由该延长体和连接体组成,其中该连接体包含一个或多个γGlu(化学式2)和/或一个或多个Ado(化学式3)和/或一个或多个εLys(化学式5)或由以上元件组成。在一些实施方案中,取代基z选自化学式7、化学式8、化学式10和化学式11。If a substituent is attached to a GLP-1/GIP receptor co-agonist (e.g., active drug Z) of a compound described herein, the substituent is referred to herein as "substituent z". In some embodiments, substituent z comprises an extension according to Formula 1 (wherein n is 14, 16, or 18) and a linker, or consists of the extension and the linker, wherein the linker comprises one or more γGlu (Formula 2) and/or one or more Ado (Formula 3) and/or one or more εLys (Formula 5) or consists of the above elements. In some embodiments, substituent z is selected from Formula 7, Formula 8, Formula 10, and Formula 11.
在一些实施方案中,本发明的化合物包含取代基b和/或取代基z。GLP-1/GIP受体 共激动剂 In some embodiments, the compounds of the present invention comprise substituent b and/or substituent z. GLP-1/GIP receptor co-agonists
如本文所用的,“GLP-1/GIP受体共激动剂”是作为GLP-1受体激动剂和GIP受体激动剂的化合物。本文所述的GLP-1/GIP受体共激动剂包含多肽和可选的所定义的取代基z,或由多肽和可选的所定义的取代基z组成。在一些实施方案中,该GLP-1/GIP受体共激动剂表现出延长的半衰期,这是通过该共激动剂的氨基酸残基与C16-C22脂肪酸(任选地通过连接体)缀合而获得的,如上所述。As used herein, a "GLP-1/GIP receptor co-agonist" is a compound that is a GLP-1 receptor agonist and a GIP receptor agonist. The GLP-1/GIP receptor co-agonist described herein comprises a polypeptide and an optional substituent z, or consists of a polypeptide and an optional substituent z, as defined. In some embodiments, the GLP-1/GIP receptor co-agonist exhibits an extended half-life obtained by conjugating the amino acid residues of the co-agonist to a C 16 -C 22 fatty acid (optionally via a linker), as described above.
在一些实施方案中,肽的羧基端具有-CO2H基团。在一些实施方案中,化合物可以任选地在C末端包含酰胺基团(C(=O)-NH2),这是用-NH2代替-OH的修饰,例如第5号母体化合物所见。In some embodiments, the carboxyl terminus of the peptide has a -CO 2 H group. In some embodiments, the compound may optionally contain an amide group (C(=O)-NH 2 ) at the C-terminus, which is a modification replacing -OH with -NH 2 , such as seen in parent compound No. 5.
在一些实施方案中,所述GLP-1/GIP受体共激动剂是In some embodiments, the GLP-1/GIP receptor co-agonist is
YX2EGTX6TSDYSX12X13LX15X16X17AX19X20X21FX23X24WLX27X28GX30X31X32X33X34X35X36X37X3 8X39(SEQ ID NO.:1) YX 2 EGTX 6 TSDYSX 12 SEQ ID NO.:1)
其具有可选的C末端的酰胺修饰,其中It has an optional C-terminal amide modification, wherein
X2为Aib或A X2 is Aib or A
X6为F或VX 6 is F or V
X12为I或YX 12 is I or Y
X13为Y、A、L、I或Aib X13 is Y, A, L, I or Aib
X15为D或EX 15 is D or E
X16为K或EX 16 is K or E
X17为Q或IX 17 is Q or I
X19为A或QX 19 is A or Q
X20为Q、R、E、H或KX 20 is Q, R, E, H or K
X21为A或EX 21 is A or E
X23为I或V X23 is I or V
X24为E、Q或NX 24 is E, Q or N
X27为L或IX 27 is L or I
X28为A或RX 28 is A or R
X30为G或不存在X 30 is G or does not exist
X31为P或不存在X 31 is P or does not exist
X32为E、S或不存在X 32 is E, S or does not exist
X33为S、K或不存在X 33 is S, K or does not exist
X34为G或不存在X 34 is G or does not exist
X35为A或不存在X 35 is A or does not exist
X36为P或不存在X 36 is P or does not exist
X37为P或不存在X 37 is P or does not exist
X38为P或不存在X 38 is P or does not exist
X39为S或不存在;X 39 is S or does not exist;
并且任选地其中包含亲脂性部分如脂肪酸(例如C16-C22羧酸)的取代基z经由位置16、20或33处的赖氨酸(K)附接至该GLP-1/GIP受体共激动剂。And optionally wherein the substituent z comprising a lipophilic moiety such as a fatty acid (eg, a C 16 -C 22 carboxylic acid) is attached to the GLP-1/GIP receptor co-agonist via a lysine (K) at position 16, 20 or 33.
在一些实施方案中,取代基z包含根据化学式1的延长体,其中n为14、16或18,以及可选的连接体,或由该延长体和可选的连接体组成,其中该连接体包含一个或多个γGlu(化学式2)和/或一个或多个Ado(化学式3)和/或一个或多个Gly(化学式4)和/或一个或多个εLys(化学式5),或由以上元件组成。在一些实施方案中,取代基z选自化学式7、化学式8、化学式10和化学式11。In some embodiments, the substituent z comprises an extension according to Formula 1, wherein n is 14, 16 or 18, and an optional linker, or is composed of the extension and an optional linker, wherein the linker comprises one or more γGlu (Formula 2) and/or one or more Ado (Formula 3) and/or one or more Gly (Formula 4) and/or one or more εLys (Formula 5), or is composed of the above elements. In some embodiments, the substituent z is selected from Formula 7, Formula 8, Formula 10 and Formula 11.
二肽BDipeptide B
在一些实施方案中,二肽B为DKP部分。在一些实施方案中,二肽B可被称为X-Y(式II),其中X和Y为α-氨基酸。在一些实施方案中,X与Y之间的酰胺键的构象优选为顺式,以通过将X的α-氨基定位在与Y的α-羰基适当接近的位置以便进行亲核攻击来促进DKP形成。在一些实施方案中,二肽B带有取代基b。在一些实施方案中,Y是N-烷基化的α-氨基酸。在一些实施方案中,Y是通过在Y的α-羧酸基团与活性药物Z的胺之间形成的酰胺键与B连接的N-烷基化的α-氨基酸。“N-烷基化的α-氨基酸”是在氨基酸的α-氨基处被烷基如C1-C12烷基或如C1-C6烷基取代的任何α-氨基酸,其中所述烷基可以是直链的或环状的,并且可以是未取代的或被额外的官能团例如氨基(如在N-(2-氨基乙基)甘氨酸中)取代。在一些实施方案中,该烷基选自甲基、乙基、2-氨基乙基、正丙基、异丙基、正丁基、仲丁基、异丁基、叔丁基、戊基、正己基。在一些实施方案中,该烷基选自甲基、乙基、2-氨基乙基、正丙基、仲丁基和正己基。在一些实施方案中,该烷基是甲基。在一些实施方案中,Y选自Sar、N-secBu-Gly、Pro、Pro(4-OH)、N-Me-Glu、N-Me-NOr、N-Me-homoAla、N-Me-Ala、N-Me-Lys、Aeg、N-Hex-homoAla、N-Pr-Ala、homoPro、N-Et-Gly、N-Pr-Gly和N-Me-Phe。在一些实施方案中,Y为Aeg或Sar。In some embodiments, dipeptide B is a DKP moiety. In some embodiments, dipeptide B may be referred to as XY (Formula II), wherein X and Y are α-amino acids. In some embodiments, the conformation of the amide bond between X and Y is preferably cis, to promote DKP formation by positioning the α-amino group of X in a position appropriately close to the α-carbonyl group of Y for nucleophilic attack. In some embodiments, dipeptide B carries a substituent b. In some embodiments, Y is an N-alkylated α-amino acid. In some embodiments, Y is an N-alkylated α-amino acid connected to B by an amide bond formed between the α-carboxylic acid group of Y and the amine of the active drug Z. "N-alkylated α-amino acid" is any α-amino acid substituted by an alkyl group such as a C 1 -C 12 alkyl group or a C 1 -C 6 alkyl group at the α-amino group of the amino acid, wherein the alkyl group may be linear or cyclic, and may be unsubstituted or substituted by additional functional groups such as amino groups (such as in N-(2-aminoethyl)glycine). In some embodiments, the alkyl group is selected from methyl, ethyl, 2-aminoethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, tert-butyl, pentyl, n-hexyl. In some embodiments, the alkyl group is selected from methyl, ethyl, 2-aminoethyl, n-propyl, sec-butyl and n-hexyl. In some embodiments, the alkyl group is methyl. In some embodiments, Y is selected from Sar, N-secBu-Gly, Pro, Pro(4-OH), N-Me-Glu, N-Me-NOr, N-Me-homoAla, N-Me-Ala, N-Me-Lys, Aeg, N-Hex-homoAla, N-Pr-Ala, homoPro, N-Et-Gly, N-Pr-Gly and N-Me-Phe. In some embodiments, Y is Aeg or Sar.
在一些实施方案中,X是任何α-氨基酸。在一些实施方案中,X是通过在X的α-羧酸基团与Y的α-氨基之间形成的酰胺键与Y连接的任何α-氨基酸。在一些实施方案中,X选自Lys、Phe(4-NH2)、D-Lys、Ala、Gly、Pro、D-Val、homoPro、D-Pro、D-homoPro、D-Ala和Aze。在一些实施方案中,X选自Gly、Asp、Leu、Lys、D-Lys和Pro。In some embodiments, X is any α-amino acid. In some embodiments, X is any α-amino acid linked to Y via an amide bond formed between the α-carboxylic acid group of X and the α-amino group of Y. In some embodiments, X is selected from Lys, Phe(4-NH 2 ), D-Lys, Ala, Gly, Pro, D-Val, homoPro, D-Pro, D-homoPro, D-Ala, and Aze. In some embodiments, X is selected from Gly, Asp, Leu, Lys, D-Lys, and Pro.
在一些实施方案中,Y选自Sar、N-sBu-Gly、Pro、Pro(4-OH)、N-Me-Glu、N-Me-NOr、N-Me-homoAla、N-Me-Ala、N-Me-Lys、N-Hex-homoAla、N-Pr-Ala、homoPro、N-Pr-Gly、N-Et-Gly和N-Me-Phe,并且X选自Lys、Phe(4-NH2)和D-Lys。另外或备选地,在一些实施方案中,Y选自Sar和Aeg,并且X选自Ala、Gly、D-Lys、Pro、D-Val、homoPro、D-Pro、D-homoPro、D-Ala和Aze。In some embodiments, Y is selected from Sar, N-sBu-Gly, Pro, Pro(4-OH), N-Me-Glu, N-Me-NOr, N-Me-homoAla, N-Me-Ala, N-Me-Lys, N-Hex-homoAla, N-Pr-Ala, homoPro, N-Pr-Gly, N-Et-Gly, and N-Me-Phe, and X is selected from Lys, Phe(4-NH 2 ), and D-Lys. Additionally or alternatively, in some embodiments, Y is selected from Sar and Aeg, and X is selected from Ala, Gly, D-Lys, Pro, D-Val, homoPro, D-Pro, D-homoPro, D-Ala, and Aze.
在一些实施方案中,任选地包含取代基b的二肽选自表5a。In some embodiments, the dipeptide optionally comprising substituent b is selected from Table 5a.
在一些实施方案中,二肽衍生物选自表5b。In some embodiments, the dipeptide derivative is selected from Table 5b.
表5a.DKP部分的二肽衍生物的非限制性实例。Table 5a. Non-limiting examples of dipeptide derivatives of the DKP moiety.
表5b.DKP部分的取代二肽的非限制性实例。Table 5b. Non-limiting examples of substituted dipeptides of the DKP moiety.
活性药物ZActive drug Z
本文描述的活性药物Z是包含如上定义的取代基z的GLP-1/GIP受体共激动剂,其中取代基z通过氨基酸残基与GLP-1/GIP受体共激动剂附接。The active drug Z described herein is a GLP-1/GIP receptor co-agonist comprising a substituent z as defined above, wherein the substituent z is attached to the GLP-1/GIP receptor co-agonist via an amino acid residue.
功能性质Functional properties
药理活性化合物的治疗用途可能会受到不合适的药代动力学性质的阻碍,例如,因为药代动力学性质不适合在施用化合物后达到所需的暴露。可使用前药技术来改善药代动力学性质,例如使其适合每周一次口服给药。施用前药后活性药物的暴露水平依赖于前药到药物的转化半衰期,因此获得合适的转化半衰期可以使化合物适合于特定的给药方案(例如每周一次给药)。施用前药后活性药物的暴露水平依赖于活性药物的观察到的终末半衰期,因此获得合适的终末半衰期可以使化合物适合于特定的给药方案(例如每周一次给药)。前药对口服施用的适合性依赖于它们在胃肠道中吸收后到达体循环的能力,因此获得合适的口服生物利用度可以使化合物适合于口服给药(例如每周一次口服给药)。The therapeutic use of pharmacologically active compounds may be hindered by inappropriate pharmacokinetic properties, for example, because the pharmacokinetic properties are not suitable for achieving the desired exposure after administration of the compound. Prodrug technology can be used to improve pharmacokinetic properties, for example, making it suitable for oral administration once a week. The exposure level of the active drug after the administration of the prodrug depends on the conversion half-life of the prodrug to the drug, so obtaining a suitable conversion half-life can make the compound suitable for a specific dosing regimen (e.g., once a week). The exposure level of the active drug after the administration of the prodrug depends on the observed terminal half-life of the active drug, so obtaining a suitable terminal half-life can make the compound suitable for a specific dosing regimen (e.g., once a week). The suitability of the prodrug for oral administration depends on their ability to reach the systemic circulation after absorption in the gastrointestinal tract, so obtaining a suitable oral bioavailability can make the compound suitable for oral administration (e.g., once a week oral administration).
根据第一功能方面,与活性药物相比,如本文所述的化合物不在任何显著的程度上对人GLP-1和/或GIP受体发挥预期的效力。另外,或备选地,在第二功能方面,如本文所述的前药在生理条件下转化为活性药物。另外,或备选地,在第三功能方面,如本文所述的前药在静脉内、皮下和/或口服给药后具有改善的药代动力学性质,如延长的终末半衰期。According to the first functional aspect, the compounds as described herein do not exert the expected efficacy on human GLP-1 and/or GIP receptors to any significant extent compared to the active drug. Additionally, or alternatively, in the second functional aspect, the prodrugs as described herein are converted to active drugs under physiological conditions. Additionally, or alternatively, in the third functional aspect, the prodrugs as described herein have improved pharmacokinetic properties after intravenous, subcutaneous and/or oral administration, such as a prolonged terminal half-life.
功能受体激活活性Functional receptor activation activity
根据第一功能方面,与活性药物相比,本发明的前药不在任何显著的程度上激活人GlP-1受体和/或人GIP受体。如本文所述的GLP-1/GIP受体激动剂的功能活性可以按照本文中“测量体外功能效力的一般方法”所述在体外进行测试。According to the first functional aspect, the prodrugs of the present invention do not activate the human GlP-1 receptor and/or the human GIP receptor to any significant extent compared to the active drug. The functional activity of the GLP-1/GIP receptor agonists as described herein can be tested in vitro as described in the "General Methods for Measuring In Vitro Functional Efficacy" herein.
术语半数最大有效浓度(EC50)通常是指参照剂量响应曲线,诱导基线与最大值之间的一半的响应的浓度。EC50用作化合物效力的量度,并且代表观察到其最大效应的50%时的浓度。The term half maximal effective concentration ( EC50 ) generally refers to the concentration that induces a response halfway between baseline and maximum with reference to a dose response curve.EC50 is used as a measure of compound potency and represents the concentration at which 50% of its maximal effect is observed.
因此,化合物的体外效力可以如本文所述确定,并确定EC50。EC50值越低,效力越好。Thus, the in vitro potency of a compound can be determined as described herein, and the EC50 determined. The lower the EC50 value, the better the potency.
为了表征此类化合物,可能还需要考虑相对于每种受体的天然激素的体外效力。To characterize such compounds, it may also be necessary to consider the in vitro potency relative to the native hormone at each receptor.
例如,可以在含有表达合适的GLP-1和/或GIP受体的膜的介质中,和/或在使用表达合适的GLP-1和/或GIP受体的全细胞的测定中确定体外效力。For example, in vitro potency can be determined in a medium containing membranes expressing the appropriate GLP-1 and/or GIP receptors, and/or in an assay using whole cells expressing the appropriate GLP-1 and/or GIP receptors.
例如,可以在报告基因测定中,例如在稳定转染的BHK细胞系中测量人GLP-1和/或GIP受体的功能响应,该BHK细胞系表达人GLP-1和/或GIP受体并且含有与启动子偶联的cAMP响应元件(CRE)DNA以及萤火虫萤光素酶(CRE萤光素酶)基因。当由于GLP-1和/或GIP受体的激活而产生cAMP时,这进而导致萤光素酶得到表达。可通过添加萤光素来测定萤光素酶,该萤光素被该酶转化成氧化萤光素并产生生物发光,该生物发光被测量为体外效力的报告指标。这类测定的一个实例在本文描述的实施例5中描述。由于化合物可包含旨在结合白蛋白的一个或多个取代基,因此还必须注意,受体活性可能会受到测定介质中人血清白蛋白(HSA)的存在与否的影响。与不存在HSA时的EC50相比,EC50的增加所表明的化合物在存在HSA时的效力降低,指示化合物与HSA的相互作用并预测在体内的作用时间延长。For example, the functional response of the human GLP-1 and/or GIP receptor can be measured in a reporter gene assay, such as in a stably transfected BHK cell line that expresses the human GLP-1 and/or GIP receptor and contains a cAMP response element (CRE) DNA coupled to a promoter and a firefly luciferase (CRE luciferase) gene. When cAMP is produced due to activation of the GLP-1 and/or GIP receptor, this in turn results in the expression of luciferase. Luciferase can be assayed by adding luciferin, which is converted by the enzyme to oxyluciferin and produces bioluminescence, which is measured as a reporter indicator of in vitro efficacy. An example of such an assay is described in Example 5 described herein. Since the compounds may contain one or more substituents intended to bind to albumin, it must also be noted that receptor activity may be affected by the presence or absence of human serum albumin (HSA) in the assay medium. A compound's potency is reduced in the presence of HSA, as indicated by an increase in the EC50 compared to the EC50 in the absence of HSA, indicating an interaction of the compound with HSA and predicting a prolonged duration of action in vivo.
在一个实施方案中,活性药物具有激活人GLP-1和GIP受体的有效体外作用。In one embodiment, the active agent has a potent in vitro effect of activating human GLP-1 and GIP receptors.
在一个实施方案中,母体化合物能够在体外激活人GLP-1和GIP受体,在如本文实施例2所述的CRE萤光素酶报告基因测定中,当在没有HSA的情况下进行时,EC50小于20pM。In one embodiment, the parent compound is capable of activating human GLP-1 and GIP receptors in vitro with an EC50 of less than 20 pM in a CRE luciferase reporter gene assay as described in Example 2 herein when performed in the absence of HSA.
在一个实施方案中,母体化合物具有针对人GLP-1和GIP受体的体外效力,使用实施例2的方法测定,对应于等于或低于100pM,更优选低于50pM,或最优选低于20pM的EC50。In one embodiment, the parent compound has an in vitro potency at human GLP-1 and GIP receptors, determined using the method of Example 2, corresponding to an EC50 equal to or below 100 pM, more preferably below 50 pM, or most preferably below 20 pM.
在一个实施方案中,在人GLP-1和GIP受体测定中的EC50均为1-25pM,如1-20pM,如1-15pM或如1-10pM。In one embodiment the EC50 in both the human GLP-1 and GIP receptor assays is 1-25 pM, such as 1-20 pM, such as 1-15 pM or such as 1-10 pM.
转化半衰期Transformation half-life
根据第二功能方面,本发明的前药具有好得惊人的转化半衰期。According to a second functional aspect, the prodrugs of the present invention have surprisingly good conversion half-lives.
前药转化为活性药物的发生速率可以通过转化半衰期来量化。如本文所用的术语“转化半衰期”是指前药浓度因转化而减半所需的时间长度。The rate at which conversion of a prodrug to an active drug occurs can be quantified by the conversion half-life. As used herein, the term "conversion half-life" refers to the length of time required for the concentration of a prodrug to be reduced by half due to conversion.
对于在人类中旨在每周一次口服给药的前药而言,如本文中‘测量转化半衰期的一般方法’中所述,在pH 7.4和37℃下测量时,理想的转化半衰期可以是24-500小时,如50-400小时,如75-300小时,或如100-200小时。For a prodrug intended for once-weekly oral administration in humans, an ideal conversion half-life may be 24-500 hours, such as 50-400 hours, such as 75-300 hours, or such as 100-200 hours, when measured at pH 7.4 and 37°C as described in 'General method for measuring conversion half-life' herein.
前药可在DKP部分的分子内环化后实现所需的转化,该部分随之从活性药物上切下,导致活性药物的释放。这样的分子内环化可以在生理条件下作为非依赖于酶的过程发生,例如通过2,5-二酮基哌嗪(DKP)的形成。在能够通过DKP形成而转化为活性药物的前药中,在转化时释放出活性药物的部分被称为DKP部分。转化半衰期尤其依赖于DKP部分的性质,因此,例如通过DKP部分的分子设计,使前药的性质适合于特定的给药方案(例如每周一次口服给药),可以改善转化半衰期(例如使其适合于每周一次口服给药)。The prodrug can achieve the desired conversion after intramolecular cyclization of the DKP moiety, which is then cleaved from the active drug, resulting in the release of the active drug. Such intramolecular cyclization can occur as an enzyme-independent process under physiological conditions, for example through the formation of 2,5-diketopiperazine (DKP). In a prodrug that can be converted to an active drug by DKP formation, the portion that releases the active drug upon conversion is called the DKP moiety. The conversion half-life is particularly dependent on the properties of the DKP moiety, and therefore, for example, the conversion half-life can be improved (for example, making it suitable for once-weekly oral administration) by molecular design of the DKP moiety to make the properties of the prodrug suitable for a specific dosing regimen (for example, once-weekly oral administration).
在一些实施方案中,转化半衰期适合于每日一次给药。在一些实施方案中,转化半衰期适合于每周一次给药。在一些实施方案中,转化半衰期>24小时。在一些实施方案中,转化半衰期>50小时。在一些实施方案中,转化半衰期>75小时。在一些实施方案中,转化半衰期>100小时。在一些实施方案中,转化半衰期<500小时。在一些实施方案中,转化半衰期<400小时。在一些实施方案中,转化半衰期<300小时。在一些实施方案中,转化半衰期<200小时。In some embodiments, the conversion half-life is suitable for once daily dosing. In some embodiments, the conversion half-life is suitable for once weekly dosing. In some embodiments, the conversion half-life is >24 hours. In some embodiments, the conversion half-life is >50 hours. In some embodiments, the conversion half-life is >75 hours. In some embodiments, the conversion half-life is >100 hours. In some embodiments, the conversion half-life is <500 hours. In some embodiments, the conversion half-life is <400 hours. In some embodiments, the conversion half-life is <300 hours. In some embodiments, the conversion half-life is <200 hours.
在一些实施方案中,转化半衰期为24-500小时。在一些实施方案中,转化半衰期为50-400小时。在一些实施方案中,转化半衰期为75-300小时。在一些实施方案中,转化半衰期为100-200小时。In some embodiments, the conversion half-life is 24-500 hours. In some embodiments, the conversion half-life is 50-400 hours. In some embodiments, the conversion half-life is 75-300 hours. In some embodiments, the conversion half-life is 100-200 hours.
观察到的终末半衰期Observed terminal half-life
许多药物显示出双阶段血浆分布曲线,该曲线最初遵循陡斜率,随后遵循缓斜率。遵循缓斜率的阶段可被称为“终末阶段”。如本文所用的术语“终末半衰期”是指化合物的血浆浓度在终末阶段中减半所需要的时间。药物在以其游离形式施用时的终末半衰期不同于该药物作为前药施用时的终末半衰期,因为当作为前药施用时,在前药在体内转化时发生游离形式的药物的持续释放。Many drugs show a biphasic plasma distribution curve that initially follows a steep slope and then a gentle slope. The phase that follows the gentle slope may be referred to as the "terminal phase". The term "terminal half-life" as used herein refers to the time required for the plasma concentration of a compound to be halved in the terminal phase. The terminal half-life of a drug when administered in its free form is different from the terminal half-life of the drug when administered as a prodrug, because when administered as a prodrug, sustained release of the drug in free form occurs when the prodrug is converted in vivo.
作为前药施用的活性药物的血浆浓度尤其是活性药物从血流中消除以及前药逐渐转化为活性药物的结果。前药的逐渐转化确保了活性药物的持续供应,因此与以游离形式施用药物时相比,减少了达到所需暴露水平所需的给药次数。活性药物向血流中的持续供应反映在观察到的终末半衰期(即,可测量的终末半衰期)中,与以游离形式施用时相比,活性药物作为前药施用时观察到的终末半衰期更长。The plasma concentration of an active drug administered as a prodrug is particularly the result of the elimination of the active drug from the bloodstream and the gradual conversion of the prodrug to the active drug. The gradual conversion of the prodrug ensures a continuous supply of the active drug, thereby reducing the number of doses required to achieve the desired exposure level compared to when the drug is administered in free form. The continuous supply of active drug to the bloodstream is reflected in the observed terminal half-life (i.e., measurable terminal half-life), which is longer when the active drug is administered as a prodrug than when it is administered in free form.
本发明的前药或前药的活性药物的药代动力学性质可通过体内药代动力学研究适当地确定。进行这样的研究以评估随着时间的推移,药物化合物如何在体内吸收、分布和消除,以及这些过程如何影响化合物在体内的浓度。在药物开发的发现和临床前阶段,可使用诸如小鼠、大鼠、猴、犬、小型猪或猪等动物模型来进行这种表征。这些模型中的任一种均可用来测试本发明前药的药代动力学性质。在这样的研究中,通常以相关制剂的形式向动物静脉内(i.v.)、皮下(s.c.)或经口(p.o.)施用单剂量的药物。在给药后的预定时间点抽取血液样品,并通过相关的定量测定分析样品的药物浓度。基于这些测量,绘制所研究的化合物的血浆浓度曲线,并对数据进行所谓的非房室药代动力学分析。对于大多数化合物,在以半对数图绘制时,血浆浓度曲线的终末部分将是直线的,这表明药物以恒定分数速率从体内去除。该速率(lambda Z或λz)等于该图终末部分的斜率的负数。由该速率,还可以按t1/2=ln(2)/λz计算出终末半衰期(参见,例如,Johan Gabrielsson和Daniel Weiner:Pharmacokinetics and Pharmacodynamic Data Analysis.Concepts&Applications,第3版,Swedish Pharmaceutical Press,Stockholm(2000))。当研究作为前药施用的活性药物时,活性药物的终末半衰期受由前药的逐渐转化所导致的活性药物的持续供应的影响,因为前药充当缓慢释放药物的储库。因此,对作为前药施用的活性药物的终末半衰期的分析最方便地被称为“观察到的终末半衰期”,因为它与以游离形式施用活性药物时不同。The pharmacokinetic properties of the prodrugs or active drugs of the prodrugs of the present invention can be appropriately determined by in vivo pharmacokinetic studies. Such studies are conducted to assess how the drug compound is absorbed, distributed and eliminated in vivo over time, and how these processes affect the concentration of the compound in vivo. In the discovery and preclinical stages of drug development, animal models such as mice, rats, monkeys, dogs, miniature pigs or pigs can be used for such characterization. Any of these models can be used to test the pharmacokinetic properties of the prodrugs of the present invention. In such studies, a single dose of the drug is usually administered intravenously (iv), subcutaneously (sc) or orally (po) to the animal in the form of a relevant formulation. Blood samples are drawn at a predetermined time point after administration, and the drug concentration of the sample is analyzed by a relevant quantitative determination. Based on these measurements, the plasma concentration curve of the compound under study is plotted, and the data is subjected to so-called non-compartmental pharmacokinetic analysis. For most compounds, when plotted in a semi-logarithmic graph, the terminal portion of the plasma concentration curve will be a straight line, indicating that the drug is removed from the body at a constant fractional rate. The rate (lambda Z or λ z ) is equal to the negative of the slope of the terminal portion of the graph. From this rate, the terminal half-life can also be calculated as t1/2 = ln(2)/λ z (see, e.g., Johan Gabrielsson and Daniel Weiner: Pharmacokinetics and Pharmacodynamic Data Analysis. Concepts & Applications, 3rd edition, Swedish Pharmaceutical Press, Stockholm (2000)). When studying an active drug administered as a prodrug, the terminal half-life of the active drug is affected by the continuous supply of the active drug caused by the gradual conversion of the prodrug, because the prodrug acts as a reservoir for slowly released drug. Therefore, the analysis of the terminal half-life of an active drug administered as a prodrug is most conveniently referred to as the "observed terminal half-life" because it is different from when the active drug is administered in free form.
在一些实施方案中,本发明的前药的终末半衰期按照本文中‘在小型猪中测量终末半衰期的一般方法’中所述来确定。当在小型猪中测定时,适合人类每周一次口服给药的观察到的终末半衰期可以>50小时,或优选>70小时,或最优选>90小时。当在小型猪中测定时,适合人类每周一次口服给药的观察到的终末半衰期可以<250小时,或者可以优选<180小时。当在小型猪中测定时,适合人类每周一次口服给药的观察到的终末半衰期可以在50-250小时的范围内,或者可以优选地在90-180小时的范围内。In some embodiments, the terminal half-life of the prodrug of the present invention is determined as described in the 'General Method for Measuring Terminal Half-Life in Minipigs' herein. When measured in minipigs, the observed terminal half-life suitable for once-weekly oral administration in humans may be >50 hours, or preferably >70 hours, or most preferably >90 hours. When measured in minipigs, the observed terminal half-life suitable for once-weekly oral administration in humans may be <250 hours, or may preferably be <180 hours. When measured in minipigs, the observed terminal half-life suitable for once-weekly oral administration in humans may be in the range of 50-250 hours, or may preferably be in the range of 90-180 hours.
口服生物利用度Oral bioavailability
采用药理活性化合物的口服治疗可能会受到较差生物利用度的阻碍。术语“生物利用度”是指化合物在给药后到达体循环的能力,并且它可以被量化为化合物剂量在给药后到达体循环的分数程度。期望用于口服给药的药物具有高口服吸收(即,口服给药后从胃肠道的高吸收),因为这可以减少达到药物的预期全身浓度所需的剂量,因此例如减小片剂尺寸并降低制造成本。Oral therapy with pharmacologically active compounds may be hampered by poor bioavailability. The term "bioavailability" refers to the ability of a compound to reach the systemic circulation after administration, and it can be quantified as the fractional extent to which a dose of the compound reaches the systemic circulation after administration. It is desirable for drugs intended for oral administration to have high oral absorption (i.e., high absorption from the gastrointestinal tract after oral administration) because this can reduce the dose required to achieve the desired systemic concentration of the drug, thereby, for example, reducing tablet size and reducing manufacturing costs.
如本文所用的术语“口服生物利用度”是指化合物在口服给药后到达体循环的能力。口服生物利用度反映了化合物在口服给药后在胃肠道中吸收的程度。换言之,高口服生物利用度与高口服吸收相关。药物的高口服生物利用度与口服给药后的高药物暴露相关。如WO2019/149880中所述,可以在比格犬中以与吸收促进剂N-(8-[2-羟基苯甲酰基]氨基)辛酸钠(SNAC)的共制剂形式测量口服生物利用度。The term "oral bioavailability" as used herein refers to the ability of a compound to reach systemic circulation after oral administration. Oral bioavailability reflects the extent to which a compound is absorbed in the gastrointestinal tract after oral administration. In other words, high oral bioavailability is associated with high oral absorption. High oral bioavailability of a drug is associated with high drug exposure after oral administration. As described in WO2019/149880, oral bioavailability can be measured in beagle dogs in the form of a co-formulation with an absorption enhancer, sodium N-(8-[2-hydroxybenzoyl]amino) caprylate (SNAC).
口服生物利用度可以按照本文中“在比格犬中测量口服生物利用度的一般方法”中所述进行测量。在一些实施方案中,如本文所述的化合物具有高口服生物利用度。在一些实施方案中,如本文所述的化合物具有与活性药物相似的口服生物利用度。在一些实施方案中,如本文所述的化合物具有不次于活性药物的口服生物利用度。在一些实施方案中,如本文所述的化合物具有至少与活性药物一样高的口服生物利用度。在一些实施方案中,如本文所述的化合物具有适合于人类每周一次口服给药的口服生物利用度。在一些实施方案中,如本文所述的化合物具有在比格犬中测定并测量为Cmax/剂量[kg/L]的口服生物利用度。在一些实施方案中,如本文所述的化合物具有在比格犬中测量为Cmax/剂量[kg/L]的口服生物利用度;其中Cmax/剂量[kg/L]>0.10,优选>0.15,最优选>0.20。在一些实施方案中,如本文所述的化合物具有在比格犬中测定并测量为AUC/剂量[kg*hr/L]的口服生物利用度。在一些实施方案中,如本文所述的化合物具有在比格犬中测定并测量为AUC/剂量[kg*hr/L]的口服生物利用度;其中AUC/剂量[kg*hr/L]>2.0,优选>5.0,最优选>10.0。Oral bioavailability can be measured as described in the "General Method for Measuring Oral Bioavailability in Beagles" herein. In some embodiments, the compounds as described herein have high oral bioavailability. In some embodiments, the compounds as described herein have oral bioavailability similar to that of the active drug. In some embodiments, the compounds as described herein have oral bioavailability that is not inferior to that of the active drug. In some embodiments, the compounds as described herein have oral bioavailability that is at least as high as that of the active drug. In some embodiments, the compounds as described herein have oral bioavailability suitable for oral administration once a week to humans. In some embodiments, the compounds as described herein have oral bioavailability determined in beagles and measured as Cmax/dose [kg/L]. In some embodiments, the compounds as described herein have oral bioavailability measured in beagles as Cmax/dose [kg/L]; wherein Cmax/dose [kg/L]>0.10, preferably>0.15, most preferably>0.20. In some embodiments, the compounds as described herein have an oral bioavailability determined in beagle dogs and measured as AUC/dose [kg*hr/L]. In some embodiments, the compounds as described herein have an oral bioavailability determined in beagle dogs and measured as AUC/dose [kg*hr/L]; wherein AUC/dose [kg*hr/L]>2.0, preferably>5.0, most preferably>10.0.
药物组合物Pharmaceutical composition
包含本文所述前药或其药学上可接受的盐和可选的一种或多种药学上可接受的辅料的药物组合物可以如本领域已知的那样制备。Pharmaceutical compositions comprising the prodrugs described herein or pharmaceutically acceptable salts thereof and optionally one or more pharmaceutically acceptable excipients can be prepared as known in the art.
术语“辅料”宽泛地指除活性治疗成分以外的任何组分。辅料可以是惰性物质、无活性物质和/或非药学活性物质。辅料可用于多种目的,例如作为载体、媒介物、填充剂、粘合剂、润滑剂、助流剂、崩解剂、流动控制剂、结晶抑制剂、增溶剂、稳定剂、着色剂、调味剂、表面活性剂、乳化剂或其组合,并且/或者用于改善给药,和/或改善活性物质的吸收。所使用的每种辅料的量可以在本领域的常规范围内变化。可用于配制口服剂型的技术和辅料在以下文献中描述:Handbook of Pharmaceutical Excipients(例如,第8版,Sheskey等人编,American Pharmaceuticals Association and Pharmaceutical Press,RoyalPharmaceutical Society of Great Britain的出版部(2017),及任何后续版本);和Remington:The Science and Practice of Pharmacy(例如,第22版,Remington和Allen编,Pharmaceutical Press(2013),及任何后续版本)。The term "excipient" refers broadly to any component other than the active therapeutic ingredient. An excipient can be an inert substance, an inactive substance, and/or a non-pharmaceutically active substance. Excipients can be used for a variety of purposes, such as as carriers, vehicles, fillers, adhesives, lubricants, glidants, disintegrants, flow control agents, crystallization inhibitors, solubilizers, stabilizers, colorants, flavoring agents, surfactants, emulsifiers, or combinations thereof, and/or for improving administration, and/or improving the absorption of active substances. The amount of each excipient used can vary within the conventional range of the art. The techniques and excipients that can be used to prepare oral dosage forms are described in the following documents: Handbook of Pharmaceutical Excipients (e.g., 8th edition, Sheskey et al., ed., American Pharmaceuticals Association and Pharmaceutical Press, Royal Pharmaceutical Society of Great Britain's Publishing Department (2017), and any subsequent editions); and Remington: The Science and Practice of Pharmacy (e.g., 22nd edition, Remington and Allen, ed., Pharmaceutical Press (2013), and any subsequent editions).
包含本文所述化合物的药物组合物可以是数种剂型,例如溶液、悬浮液、片剂和胶囊。包含本发明前药的药物组合物可以施用于有需要的患者的若干部位,例如,局部部位,如皮肤或粘膜部位;旁路吸收的部位,如动脉、静脉或心脏中;以及涉及吸收的部位,如皮肤中、皮肤下、肌肉中、经口或腹部中。给药剂量可包含0.1ug/kg至100mg/kg的本发明化合物。Pharmaceutical compositions comprising the compounds described herein can be in several dosage forms, such as solutions, suspensions, tablets and capsules. Pharmaceutical compositions comprising the prodrugs of the present invention can be applied to several sites of patients in need, for example, local sites, such as skin or mucosal sites; sites of bypass absorption, such as arteries, veins or hearts; and sites involving absorption, such as in the skin, under the skin, in the muscle, orally or in the abdomen. The dosage may contain 0.1 ug/kg to 100 mg/kg of the compounds of the present invention.
在一些实施方案中,药物组合物可以是固体制剂,例如,冷冻干燥或喷雾干燥的组合物,其可以原样使用,或由医师或患者在使用前向其添加溶剂和/或稀释剂。在一个实施方案中,药物组合物是片剂的形式。在进一步的实施方案中,药物组合物可以是包含本发明前药、N-[8-(2-羟基苯甲酰基)氨基]辛酸的盐如N-[8-(2-羟基苯甲酰基)氨基]辛酸钠(SNAC)和一种或多种本领域已知的其他辅料或由以上组分组成的固体制剂,例如使用WO2012/080471、WO 2013/189988或WO 2019/149880中描述的任何一种或多种制剂。在一个实施方案中,药物制剂是包含本发明前药、SNAC和一种或多种其他辅料的片剂。In some embodiments, the pharmaceutical composition can be a solid preparation, for example, a freeze-dried or spray-dried composition, which can be used as is, or a solvent and/or diluent is added thereto by a physician or patient before use. In one embodiment, the pharmaceutical composition is in the form of a tablet. In a further embodiment, the pharmaceutical composition can be a solid preparation comprising a prodrug of the present invention, a salt of N-[8-(2-hydroxybenzoyl)amino]octanoic acid such as sodium N-[8-(2-hydroxybenzoyl)amino]octanoate (SNAC) and one or more other excipients known in the art or composed of the above components, for example, using any one or more of the preparations described in WO2012/080471, WO 2013/189988 or WO 2019/149880. In one embodiment, the pharmaceutical formulation is a tablet comprising a prodrug of the present invention, SNAC and one or more other excipients.
或者,药物组合物是液体制剂,如水性制剂。适合注射的液体组合物可采用制药工业的常规技术来制备,该常规技术包括酌情将成分溶解并混合以得到所需终产物。因此,根据一种程序,将根据本发明的化合物溶解在适当pH的适当缓冲液中。例如,可以通过除菌过滤对组合物进行灭菌。Alternatively, the pharmaceutical composition is a liquid preparation, such as an aqueous preparation. Liquid compositions suitable for injection can be prepared using conventional techniques of the pharmaceutical industry, which include dissolving and mixing the components as appropriate to obtain the desired end product. Therefore, according to a procedure, the compound according to the present invention is dissolved in a suitable buffer at an appropriate pH. For example, the composition can be sterilized by sterilizing filtration.
药学上可接受的盐Pharmaceutically acceptable salts
在一些实施方案中,如本文所述的前药是药学上可接受的盐的形式。例如,通过碱与酸之间的化学反应来形成盐,例如:2NH3+H2SO4→(NH4)2SO4。该盐可以是碱式盐、酸式盐,或者其可以两者都不是(即,中性盐)。在水中,碱式盐产生氢氧根离子而酸式盐产生水合氢离子。可通过分别在阴离子或阳离子基团之间添加阳离子或阴离子来形成前药的盐。这些基团可以位于肽中,和/或衍生物的取代基中。In some embodiments, the prodrugs described herein are in the form of pharmaceutically acceptable salts. For example, a salt is formed by a chemical reaction between a base and an acid, for example: 2NH 3 +H 2 SO 4 →(NH 4 ) 2 SO 4 . The salt may be a basic salt, an acidic salt, or it may be neither (i.e., a neutral salt). In water, basic salts produce hydroxide ions and acidic salts produce hydronium ions. Salts of prodrugs may be formed by adding cations or anions between anionic or cationic groups, respectively. These groups may be located in the peptide, and/or in substituents of the derivative.
阴离子基团的非限制性实例包括在取代基(如果有的话)中以及在肽中的任何游离羧酸基团。该肽可包含C末端的游离羧酸基团(如果存在的话),以及诸如天冬氨酸和谷氨酸等氨基酸残基的任何游离羧酸基团。Non-limiting examples of anionic groups include any free carboxylic acid groups in the substituents (if any) and in the peptide. The peptide may contain a free carboxylic acid group at the C-terminus (if any), as well as any free carboxylic acid groups of amino acid residues such as aspartic acid and glutamic acid.
阳离子基团的非限制性实例包括在取代基(如果有的话)中以及在肽中的任何游离氨基。该肽可包含N末端的游离氨基(如果存在的话),以及诸如组氨酸、精氨酸和赖氨酸等氨基酸残基的任何游离咪唑、胍或氨基。Non-limiting examples of cationic groups include any free amino groups in the substituents (if any) and in the peptide. The peptide may contain a free amino group at the N-terminus (if any), and any free imidazole, guanidine or amino groups of amino acid residues such as histidine, arginine and lysine.
在特定实施方案中,本发明的前药是药学上可接受的盐的形式。In certain embodiments, the prodrugs of the present invention are in the form of pharmaceutically acceptable salts.
药物适应症Drug Indications
本发明的另一方面涉及用作药物的如本文所述的化合物。如本文所用的,术语“治疗”是指对任何有需要的人类受试者的医药治疗。该治疗可以是防止性的、预防性的、姑息性的、对症的和/或治愈性的。根据受试者的健康状态,所述治疗的时机和目的可因个体而异。Another aspect of the present invention relates to a compound as described herein for use as a medicament. As used herein, the term "treatment" refers to medical treatment of any human subject in need thereof. The treatment may be preventive, prophylactic, palliative, symptomatic and/or curative. The timing and purpose of the treatment may vary from individual to individual, depending on the subject's health status.
在一些实施方案中,本文所述的化合物用于以下医药治疗:In some embodiments, the compounds described herein are used in the following medical treatments:
(i)预防和/或治疗所有形式的糖尿病,如高血糖症、2型糖尿病、糖耐量减低、1型糖尿病、非胰岛素依赖性糖尿病、MODY(青年成熟发作型糖尿病)、妊娠糖尿病,和/或用于减少HbA1C;(i) prevention and/or treatment of all forms of diabetes, such as hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, non-insulin-dependent diabetes mellitus, MODY (maturity-onset diabetes of the young), gestational diabetes, and/or for the reduction of HbA1C;
(ii)延缓或预防糖尿病进展,如2型糖尿病的进展,延缓糖耐量减低(IGT)进展成需要胰岛素的2型糖尿病,延缓或预防胰岛素抵抗,和/或延缓无需胰岛素的2型糖尿病进展成需要胰岛素的2型糖尿病;(ii) delaying or preventing the progression of diabetes, such as the progression of type 2 diabetes, delaying the progression of impaired glucose tolerance (IGT) to insulin-requiring type 2 diabetes, delaying or preventing insulin resistance, and/or delaying the progression of insulin-not-requiring type 2 diabetes to insulin-requiring type 2 diabetes;
(iii)例如通过减少食物摄入量、减轻体重、抑制食欲、诱导饱腹感来预防和/或治疗饮食失调,如超重或肥胖症;治疗或预防暴食症、神经性贪食症和/或由抗精神病药或类固醇给药诱发的肥胖症;减少胃运动;延缓胃排空;增加身体活动;和/或预防和/或治疗肥胖症的共病,如骨关节炎和/或尿失禁;(iii) prevention and/or treatment of eating disorders, such as overweight or obesity, e.g. by reducing food intake, reducing body weight, suppressing appetite, inducing satiety; treating or preventing binge eating disorder, bulimia nervosa and/or obesity induced by antipsychotic or steroid administration; reducing gastric motility; delaying gastric emptying; increasing physical activity; and/or prevention and/or treatment of comorbidities of obesity, such as osteoarthritis and/or urinary incontinence;
(iv)成功减肥(无论是药物引起的还是饮食和运动引起的)后的体重维持——即,防止成功减肥后的体重增加。(iv) Weight maintenance after successful weight loss (whether induced by drugs or by diet and exercise)—that is, preventing weight gain after successful weight loss.
(v)预防和/或治疗肝脏病症,如肝脂肪变性、非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、肝脏炎症或脂肪肝。(v) preventing and/or treating liver disorders such as hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver inflammation or fatty liver.
在一些实施方案中,所述化合物用于预防和/或治疗糖尿病和/或肥胖症的方法中。在一些实施方案中,所述化合物用于治疗糖尿病和/或肥胖症的方法中。In some embodiments, the compounds are used in a method for preventing and/or treating diabetes and/or obesity. In some embodiments, the compounds are used in a method for treating diabetes and/or obesity.
在一些实施方案中,所述化合物用于治疗或预防2型糖尿病的方法中。在一些实施方案中,所述化合物用于治疗2型糖尿病的方法中。在一些实施方案中,所述化合物用于治疗或预防肥胖症的方法中。在一些实施方案中,所述化合物用于治疗肥胖症的方法中。在一些实施方案中,所述化合物用于体重管理方法中。在一些实施方案中,所述化合物用于降低食欲的方法中。在一些实施方案中,所述化合物用于减少食物摄入量的方法中。In some embodiments, the compound is used in a method for treating or preventing type 2 diabetes. In some embodiments, the compound is used in a method for treating type 2 diabetes. In some embodiments, the compound is used in a method for treating or preventing obesity. In some embodiments, the compound is used in a method for treating obesity. In some embodiments, the compound is used in a weight management method. In some embodiments, the compound is used in a method for reducing appetite. In some embodiments, the compound is used in a method for reducing food intake.
生产过程Production process
例如,可以通过经典的肽合成,例如使用t-Boc或Fmoc化学法或其他确立技术的固相肽合成,来产生本发明的前药(或其片段),参见,例如,Greene和Wuts,“ProtectiveGroups in Organic Synthesis”,John Wiley&Sons,1999;Florencio Zaragoza“Organic Synthesis on Solid Phase”,Wiley-VCH Verlag GmbH,2000;以及由W.C.Chan和P.D.White编著的“Fmoc Solid Phase Peptide Synthesis”,OxfordUniversity Press,2000。For example, the prodrugs of the present invention (or fragments thereof) can be produced by classical peptide synthesis, such as solid phase peptide synthesis using t-Boc or Fmoc chemistry or other established techniques, see, e.g., Greene and Wuts, "Protective Groups in Organic Synthesis", John Wiley & Sons, 1999; Florencio Zaragoza “Organic Synthesis on Solid Phase”, Wiley-VCH Verlag GmbH, 2000; and “Fmoc Solid Phase Peptide Synthesis” edited by WC Chan and PD White, Oxford University Press, 2000.
实验部分中包括制备前药的方法的具体实例。Specific examples of methods for preparing prodrugs are included in the experimental section.
在一些实施方案中,制备本文所述化合物的方法包括固相肽合成步骤。二肽部分和/或取代基可以作为固相肽合成的部分来顺序构建,或者单独产生并在肽合成后经由肽的适当官能团来附接。In some embodiments, the method of preparing the compounds described herein includes a solid phase peptide synthesis step. The dipeptide moiety and/or substituents can be sequentially constructed as part of solid phase peptide synthesis, or generated separately and attached via appropriate functional groups of the peptide after peptide synthesis.
在一个实施方案中,所述化合物通过两步过程产生,由此两个肽片段在取代基附接到肽片段之一上之后连接。In one embodiment, the compound is produced by a two-step process whereby the two peptide fragments are linked after a substituent is attached to one of the peptide fragments.
实施方案Implementation
通过以下非限制性实施方案进一步描述本发明:The present invention is further described by the following non-limiting embodiments:
1.式I化合物:1. Compounds of formula I:
B-Z(式I)B-Z (Formula I)
或其药学上可接受的盐、酯或酰胺,or a pharmaceutically acceptable salt, ester or amide thereof,
其中B为二肽,所述二肽任选地包含取代基b;wherein B is a dipeptide, the dipeptide optionally comprising a substituent b;
其中Z为GLP-1/GIP受体共激动剂,所述GLP-1/GIP受体共激动剂任选地包含取代基z;并且wherein Z is a GLP-1/GIP receptor co-agonist, the GLP-1/GIP receptor co-agonist optionally comprising a substituent z; and
其中所述GLP-1/GIP受体共激动剂的N端氨基通过肽键与B连接。The N-terminal amino group of the GLP-1/GIP receptor co-agonist is connected to B via a peptide bond.
2.根据实施方案1所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述GLP-1/GIP受体共激动剂的氨基酸序列为2. The compound according to embodiment 1, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the amino acid sequence of the GLP-1/GIP receptor co-agonist is
YX2EGTX6TSDYSX12X13LX15X16X17AX19X20X21FX23X24WLX27X28GX30X31X32X33X34X35X36X37X3 8X39(SEQ ID NO.:1),其中 YX 2 EGTX 6 TSDYSX 12 SEQ ID NO.:1), where
X2为Aib或A X2 is Aib or A
X6为F或VX 6 is F or V
X12为I或YX 12 is I or Y
X13为Y、A、L、I或Aib X13 is Y, A, L, I or Aib
X15为D或EX 15 is D or E
X16为K或EX 16 is K or E
X17为Q或IX 17 is Q or I
X19为A或QX 19 is A or Q
X20为Q、R、E、H或KX 20 is Q, R, E, H or K
X21为A或EX 21 is A or E
X23为I或V X23 is I or V
X24为E、Q或NX 24 is E, Q or N
X27为L或IX 27 is L or I
X28为A或RX 28 is A or R
X30为G或不存在X 30 is G or does not exist
X31为P或不存在X 31 is P or does not exist
X32为E、S或不存在X 32 is E, S or does not exist
X33为S、K或不存在X 33 is S, K or does not exist
X34为G或不存在X 34 is G or does not exist
X35为A或不存在X 35 is A or does not exist
X36为P或不存在X 36 is P or does not exist
X37为P或不存在X 37 is P or does not exist
X38为P或不存在X 38 is P or does not exist
X39为S或不存在。X 39 is S or absent.
3.根据实施方案1所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述GLP-1/GIP受体共激动剂的氨基酸序列为3. The compound according to embodiment 1, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the amino acid sequence of the GLP-1/GIP receptor co-agonist is
Y-Aib-EGTFTSDYSIX13LX15X16X17AX19X20X21FX23X24WLX27AGGP SX33GAPPPS(SEQ IDNO.:2),其中 Y - Aib - EGTFTSDYSIX 13 LX 15
X13为L或Aib,X 13 is L or Aib,
X15为D或E,X 15 is D or E,
X16为K或E,X 16 is K or E,
X17为Q或I,X 17 is Q or I,
X19为A或Q,X 19 is A or Q,
X20为R或KX 20 for R or K
X21为A或EX 21 is A or E
X23为I或V X23 is I or V
X24为E或QX 24 is E or Q
X27为L或I;X 27 is L or I;
X33为S或K。X 33 is S or K.
4.根据实施方案1所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述GLP-1/GIP受体共激动剂的氨基酸序列为4. The compound according to embodiment 1, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the amino acid sequence of the GLP-1/GIP receptor co-agonist is
Y-Aib-EGTFTSDYSILLEX16QAAREFIEWLLAGGPSX33GAPPPS(SEQ ID NO.:3),其中Y-Aib-EGTFTSDYSILLEX 16 QAAREFIEWLLAGGPSX 33 GAPPPS (SEQ ID NO.: 3), wherein
X16为K或E,X 16 is K or E,
X33为S或K。X 33 is S or K.
5.根据实施方案2至4中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中X16为E且X33为K。5. The compound according to any one of Embodiments 2 to 4, or a pharmaceutically acceptable salt, ester or amide thereof, wherein X 16 is E and X 33 is K.
6.根据实施方案2至4中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中X16为K且X33为S。6. The compound according to any one of Embodiments 2 to 4, or a pharmaceutically acceptable salt, ester or amide thereof, wherein X 16 is K and X 33 is S.
7.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述GLP-1/GIP受体共激动剂的氨基酸序列为Y-Aib-EGTFTSDYSI-Aib-LDKIAQKAFVQWLIAGGPSSGAPPPS(SEQ ID NO.:4)。7. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the amino acid sequence of the GLP-1/GIP receptor co-agonist is Y-Aib-EGTFTSDYSI-Aib-LDKIAQKAFVQWLIAGGPSSGAPPPS (SEQ ID NO.: 4).
8.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述GLP-1/GIP受体共激动剂的氨基酸序列选自Y-Aib-EGTFTSDYSI-Aib-LDKIAQKAFVQWLIAGGPSSGAPPPS(SEQ ID NO.:4)、8. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the amino acid sequence of the GLP-1/GIP receptor co-agonist is selected from Y-Aib-EGTFTSDYSI-Aib-LDKIAQKAFVQWLIAGGPSSGAPPPS (SEQ ID NO.: 4),
Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPSKGAPPPS(SEQ ID NO.:5)和Y-Aib-EGTFTSDYSILLEKQAAREFIEWLLAGGPSSGAPPPS(SEQ ID NO.:6)。Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPSKGAPPPS (SEQ ID NO.:5) and Y-Aib-EGTFTSDYSILLEKQAAREFIEWLLAGGPSSGAPPPS (SEQ ID NO.:6).
9.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述GLP-1/GIP受体共激动剂的氨基酸序列为Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPSKGAPPPS(SEQ ID NO.:5)或Y-Aib-EGTFTSDYSILLEKQAAREFIEWLLAGGPSSGAPPPS(SEQ IDNO.:6)。9. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the amino acid sequence of the GLP-1/GIP receptor co-agonist is Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPSKGAPPPS (SEQ ID NO.: 5) or Y-Aib-EGTFTSDYSILLEKQAAREFIEWLLAGGPSSGAPPPS (SEQ ID NO.: 6).
10.根据实施方案1至9中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述GLP-1/GIP受体共激动剂包含取代基z,并且其中所述取代基z通过赖氨酸(K)连接至所述GLP-1/GIP受体共激动剂。10. A compound according to any one of embodiments 1 to 9, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the GLP-1/GIP receptor co-agonist comprises a substituent z, and wherein the substituent z is linked to the GLP-1/GIP receptor co-agonist via lysine (K).
11.根据实施方案2至10中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中X16和/或X20和/或X33为赖氨酸。11. The compound according to any one of Embodiments 2 to 10, or a pharmaceutically acceptable salt, ester or amide thereof, wherein X 16 and/or X 20 and/or X 33 is lysine.
12.根据实施方案2、3、11或6中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中X16为赖氨酸。12. The compound according to any one of Embodiments 2, 3, 11 or 6, or a pharmaceutically acceptable salt, ester or amide thereof, wherein X 16 is lysine.
13.根据实施方案2、11或7中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中X20为赖氨酸。13. The compound according to any one of Embodiments 2, 11 or 7, or a pharmaceutically acceptable salt, ester or amide thereof, wherein X 20 is lysine.
14.根据实施方案2、3、11或5中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中X33为赖氨酸。14. The compound according to any one of Embodiments 2, 3, 11 or 5, or a pharmaceutically acceptable salt, ester or amide thereof, wherein X 33 is lysine.
15.根据实施方案1至14中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述取代基z通过位置16、20或33处的赖氨酸(K)连接至所述GLP-1/GIP受体共激动剂。15. A compound according to any one of embodiments 1 to 14, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the substituent z is linked to the GLP-1/GIP receptor co-agonist via lysine (K) at position 16, 20 or 33.
16.根据实施方案1至15中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中GLP-1/GIP受体共激动剂具有C末端的酰胺修饰。16. A compound according to any one of embodiments 1 to 15, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the GLP-1/GIP receptor co-agonist has an amide modification at the C-terminus.
17.根据实施方案5、8或9中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中位置33处的赖氨酸通过用化学式8、化学式7或化学式10与赖氨酸侧链的ε-氨基缀合而被化学修饰。17. The compound according to any one of Embodiments 5, 8 or 9, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the lysine at position 33 is chemically modified by conjugating to the ε-amino group of the lysine side chain with Chemical Formula 8, Chemical Formula 7 or Chemical Formula 10.
18.根据实施方案6、8或9中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中位置16处的赖氨酸通过用化学式7与赖氨酸侧链的ε-氨基缀合而被化学修饰。18. A compound according to any one of Embodiments 6, 8 or 9, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the lysine at position 16 is chemically modified by conjugation with Chemical Formula 7 to the ε-amino group of the lysine side chain.
19.根据实施方案7或实施方案8所述的化合物,或其药学上可接受的盐、酯或酰胺,其中位置20处的赖氨酸通过用化学式11与赖氨酸侧链的ε-氨基缀合而被化学修饰。19. The compound according to Embodiment 7 or Embodiment 8, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the lysine at position 20 is chemically modified by conjugating with Chemical Formula 11 to the ε-amino group of the lysine side chain.
20.根据实施方案1至19中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述二肽B为式II:20. A compound according to any one of embodiments 1 to 19, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the dipeptide B is of formula II:
X-Y(式II),X-Y (Formula II),
其中X是通过在X的α-羧酸基团与Y的α-氨基之间形成的酰胺键与Y连接的任何α-氨基酸,wherein X is any α-amino acid linked to Y via an amide bond formed between the α-carboxylic acid group of X and the α-amino group of Y,
其中Y是通过在Y的α-羧酸基团与所述GLP-1/GIP受体共激动剂的N端氨基之间形成的肽键与Z连接的N-烷基化的α-氨基酸。wherein Y is an N-alkylated α-amino acid linked to Z via a peptide bond formed between the α-carboxylic acid group of Y and the N-terminal amino group of the GLP-1/GIP receptor co-agonist.
21.根据实施方案1至16中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述二肽B为式II:21. A compound according to any one of embodiments 1 to 16, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the dipeptide B is of formula II:
X-Y(式II),X-Y (Formula II),
其中X是通过在X的α-羧酸基团与Y的α-氨基之间形成的酰胺键与Y连接的任何α-氨基酸,wherein X is any α-amino acid linked to Y via an amide bond formed between the α-carboxylic acid group of X and the α-amino group of Y,
其中Y是通过在Y的α-羧酸基团与Z的N端氨基之间形成的肽键与Z连接的N-烷基化的α-氨基酸。wherein Y is an N-alkylated α-amino acid linked to Z via a peptide bond formed between the α-carboxylic acid group of Y and the N-terminal amino group of Z.
22.根据实施方案20或实施方案21所述的化合物,或其药学上可接受的盐、酯或酰胺,其中Y选自肌氨酸、N-仲丁基甘氨酸、脯氨酸、反式-4-羟基脯氨酸、N-甲基谷氨酸、N-甲基正亮氨酸、N-甲基高丙氨酸、N-甲基丙氨酸、N-甲基赖氨酸、N-(2-氨基乙基)甘氨酸、N-己基高丙氨酸、N-丙基丙氨酸、高脯氨酸、N-丙基甘氨酸、N-乙基甘氨酸和N-甲基苯丙氨酸。22. The compound of embodiment 20 or embodiment 21, or a pharmaceutically acceptable salt, ester or amide thereof, wherein Y is selected from sarcosine, N-sec-butylglycine, proline, trans-4-hydroxyproline, N-methylglutamate, N-methylnorleucine, N-methylhomoalanine, N-methylalanine, N-methyllysine, N-(2-aminoethyl)glycine, N-hexylhomoalanine, N-propylalanine, homoproline, N-propylglycine, N-ethylglycine and N-methylphenylalanine.
23.根据实施方案20至22中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中X选自赖氨酸、4-氨基苯丙氨酸、D-赖氨酸、丙氨酸、甘氨酸、脯氨酸、D-缬氨酸、高脯氨酸、D-脯氨酸、D-高脯氨酸、D-丙氨酸和氮杂环丁烷-2-羧酸。23. A compound according to any one of embodiments 20 to 22, or a pharmaceutically acceptable salt, ester or amide thereof, wherein X is selected from lysine, 4-aminophenylalanine, D-lysine, alanine, glycine, proline, D-valine, homoproline, D-proline, D-homoproline, D-alanine and azetidine-2-carboxylic acid.
24.根据实施方案20至23中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中Y选自肌氨酸、N-仲丁基甘氨酸、脯氨酸、反式-4-羟基脯氨酸、N-甲基谷氨酸、N-甲基正亮氨酸、N-甲基高丙氨酸、N-甲基丙氨酸、N-甲基赖氨酸、N-己基高丙氨酸、N-丙基丙氨酸、高脯氨酸、N-丙基甘氨酸、N-乙基甘氨酸和N-甲基苯丙氨酸。24. A compound according to any one of embodiments 20 to 23, or a pharmaceutically acceptable salt, ester or amide thereof, wherein Y is selected from sarcosine, N-sec-butylglycine, proline, trans-4-hydroxyproline, N-methylglutamate, N-methylnorleucine, N-methylhomoalanine, N-methylalanine, N-methyllysine, N-hexylhomoalanine, N-propylalanine, homoproline, N-propylglycine, N-ethylglycine and N-methylphenylalanine.
25.根据实施方案20至24中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中Y为肌氨酸或N-(2-氨基乙基)甘氨酸。25. The compound of any one of Embodiments 20 to 24, or a pharmaceutically acceptable salt, ester or amide thereof, wherein Y is sarcosine or N-(2-aminoethyl)glycine.
26.根据实施方案20至25中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中X选自赖氨酸、D-赖氨酸、丙氨酸、亮氨酸、甘氨酸、脯氨酸和天冬氨酸。26. The compound according to any one of Embodiments 20 to 25, or a pharmaceutically acceptable salt, ester or amide thereof, wherein X is selected from lysine, D-lysine, alanine, leucine, glycine, proline and aspartic acid.
27.根据实施方案20至26中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中X选自赖氨酸、D-赖氨酸和甘氨酸。27. The compound according to any one of embodiments 20 to 26, or a pharmaceutically acceptable salt, ester or amide thereof, wherein X is selected from lysine, D-lysine and glycine.
28.根据实施方案1至27中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中二肽能够经历分子内环化以形成2,5-二酮基哌嗪(DKP),使得A与Z之间的酰胺键断裂。28. A compound according to any one of embodiments 1 to 27, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the dipeptide is capable of undergoing intramolecular cyclization to form 2,5-diketopiperazine (DKP), resulting in cleavage of the amide bond between A and Z.
29.根据实施方案1至27中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中二肽能够经历分子内环化以形成2,5-二酮基哌嗪(DKP),使得A与Z之间的肽键断裂。29. A compound according to any one of embodiments 1 to 27, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the dipeptide is capable of undergoing intramolecular cyclization to form 2,5-diketopiperazine (DKP), resulting in cleavage of the peptide bond between A and Z.
30.根据实施方案1至29中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述二肽包含取代基b。30. A compound according to any one of embodiments 1 to 29, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the dipeptide comprises a substituent b.
31.根据实施方案1至29中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述二肽带有取代基b。31. A compound according to any one of embodiments 1 to 29, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the dipeptide bears a substituent b.
32.根据实施方案1至29中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述二肽具有取代基b。32. A compound according to any one of embodiments 1 to 29, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the dipeptide has a substituent b.
33.根据实施方案21至30中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中取代基b任选地通过酰胺键与X共价连接。33. A compound according to any one of embodiments 21 to 30, or a pharmaceutically acceptable salt, ester or amide thereof, wherein substituent b is covalently linked to X, optionally through an amide bond.
34.根据实施方案21至30中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中取代基b任选地通过酰胺键与Y共价连接。34. A compound according to any one of embodiments 21 to 30, or a pharmaceutically acceptable salt, ester or amide thereof, wherein substituent b is covalently linked to Y, optionally through an amide bond.
35.根据实施方案1至34中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述取代基b是白蛋白结合部分。35. A compound according to any one of embodiments 1 to 34, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the substituent b is an albumin binding moiety.
36.根据实施方案1至35中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述取代基b包含延长体和可选的连接体或由延长体和可选的连接体组成。36. A compound according to any one of embodiments 1 to 35, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the substituent b comprises or consists of an extension and an optional linker.
37.根据实施方案36所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述延长体是脂肪酸,如C16-C22羧酸。37. The compound according to embodiment 36, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the elongate is a fatty acid, such as a C 16 -C 22 carboxylic acid.
38.根据实施方案36或实施方案37所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述延长体是化学式1。38. The compound according to Embodiment 36 or Embodiment 37, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the elongated body is Formula 1.
39.根据实施方案1至38中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述取代基包含连接体,并且任选地其中所述连接体包含连接体元件或由连接体元件组成。39. A compound according to any one of embodiments 1 to 38, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the substituent comprises a linker, and optionally wherein the linker comprises or consists of a linker element.
40.根据实施方案38至39中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述连接体为式IV40. A compound according to any one of embodiments 38 to 39, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the linker is of formula IV
A1-A2-A3-A4-A5(式IV),A 1 -A 2 -A 3 -A 4 -A 5 (Formula IV),
其中A1通过酰胺键与所述二肽的氨基酸共价结合,并且任选地还通过酰胺键与所述延长体共价结合,并且选自化学式2、化学式3、化学式4和化学式5;其中A5与化学式1共价结合并且为化学式2或不存在;其中A2、A3和A4各自单独地选自化学式2、化学式3、化学式4和化学式5,或者不存在。wherein A1 is covalently bonded to the amino acid of the dipeptide via an amide bond, and optionally also covalently bonded to the elongate via an amide bond, and is selected from the group consisting of Chemical Formula 2, Chemical Formula 3, Chemical Formula 4, and Chemical Formula 5; wherein A5 is covalently bonded to Chemical Formula 1 and is Chemical Formula 2 or is absent; wherein A2 , A3 , and A4 are each individually selected from the group consisting of Chemical Formula 2, Chemical Formula 3, Chemical Formula 4, and Chemical Formula 5, or are absent.
41.根据实施方案1至40中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述取代基b选自化学式16、化学式17、化学式18、化学式19、化学式20、化学式21和化学式22。41. The compound according to any one of Embodiments 1 to 40, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the substituent b is selected from Formula 16, Formula 17, Formula 18, Formula 19, Formula 20, Formula 21 and Formula 22.
42.根据实施方案1至41中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述化合物选自:42. A compound according to any one of embodiments 1 to 41, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the compound is selected from:
第1号化合物Compound No. 1
第2号化合物Compound No. 2
第3号化合物Compound No. 3
第4号化合物Compound No. 4
第5号化合物Compound No. 5
第6号化合物Compound No. 6
第7号化合物Compound No. 7
第8号化合物Compound No. 8
第9号化合物Compound No. 9
第10号化合物Compound No. 10
第11号化合物Compound No. 11
第12号化合物Compound No. 12
第13号化合物Compound No. 13
第14号化合物Compound No. 14
第15号化合物Compound No. 15
第16号化合物Compound No. 16
第17号化合物Compound No. 17
和and
第18号化合物Compound No. 18
43.根据实施方案1至42中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述化合物选自第1、2、3、9和10号化合物。43. A compound according to any one of embodiments 1 to 42, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the compound is selected from compound Nos. 1, 2, 3, 9 and 10.
44.根据实施方案1至43中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述化合物是第1号化合物。44. A compound according to any one of Embodiments 1 to 43, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the compound is Compound No. 1.
45.根据实施方案1至43中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述化合物是第2号化合物。45. A compound according to any one of Embodiments 1 to 43, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the compound is Compound No. 2.
46.根据实施方案1至43中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述化合物是第3号化合物。46. A compound according to any one of embodiments 1 to 43, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the compound is compound No. 3.
47.根据实施方案1至43中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述化合物是第4号化合物。47. A compound according to any one of Embodiments 1 to 43, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the compound is Compound No. 4.
48.根据实施方案1至43中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述化合物是第5号化合物。48. A compound according to any one of Embodiments 1 to 43, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the compound is Compound No. 5.
49.根据实施方案1至48中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述化合物是前药并且在体外不发挥任何显著的效力。49. A compound according to any one of embodiments 1 to 48, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the compound is a prodrug and does not exert any significant efficacy in vitro.
50.根据实施方案1至49中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述化合物是前药并且具有转化半衰期。50. A compound according to any one of embodiments 1 to 49, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the compound is a prodrug and has a conversion half-life.
51.根据实施方案50所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述转化半衰期是在体外在pH 7.4和37℃下测得的。51. The compound of embodiment 50, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the conversion half-life is measured in vitro at pH 7.4 and 37°C.
52.根据实施方案50或51所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述转化半衰期是按照本文中“测量转化半衰期的一般方法”所述测得的。52. The compound of embodiment 50 or 51, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the conversion half-life is measured as described in the "General method for measuring conversion half-life" herein.
53.根据实施方案50至52中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述转化半衰期适合于每日一次给药。53. A compound according to any one of embodiments 50 to 52, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the conversion half-life is suitable for once-daily dosing.
54.根据实施方案50至52中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述转化半衰期适合于每周一次给药。54. A compound according to any one of embodiments 50 to 52, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the conversion half-life is suitable for once-weekly dosing.
55.根据实施方案50至52中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中在体外测得的转化半衰期为90-4300小时。55. A compound according to any one of embodiments 50 to 52, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the conversion half-life measured in vitro is 90-4300 hours.
56.根据实施方案50至52中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中在体外测得的转化半衰期为90-4300小时。56. A compound according to any one of embodiments 50 to 52, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the conversion half-life measured in vitro is 90-4300 hours.
57.根据实施方案50至52中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中在体外测得的转化半衰期为300-1100小时。57. A compound according to any one of embodiments 50 to 52, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the conversion half-life measured in vitro is 300-1100 hours.
58.根据实施方案50至52中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中在体外测得的转化半衰期为450-650小时。58. A compound according to any one of embodiments 50 to 52, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the conversion half-life measured in vitro is 450-650 hours.
59.根据实施方案50至52中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中在体外测得的转化半衰期为至少100小时。59. A compound according to any one of embodiments 50 to 52, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the conversion half-life measured in vitro is at least 100 hours.
60.根据实施方案50至52中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中在体外测得的转化半衰期为至少200小时。60. A compound according to any one of embodiments 50 to 52, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the conversion half-life measured in vitro is at least 200 hours.
61.根据实施方案50至52中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中在体外测得的转化半衰期为至少300小时。61. A compound according to any one of embodiments 50 to 52, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the conversion half-life measured in vitro is at least 300 hours.
62.根据实施方案1至61中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述化合物具有终末半衰期。62. A compound according to any one of embodiments 1 to 61, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the compound has a terminal half-life.
63.根据实施方案1至61中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述化合物具有终末半衰期,并且所述终末半衰期适合于每日一次给药。63. A compound according to any one of Embodiments 1 to 61, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the compound has a terminal half-life, and the terminal half-life is suitable for once-daily dosing.
64.根据实施方案1至61中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述化合物具有终末半衰期,并且所述终末半衰期适合于每周一次给药。64. A compound according to any one of embodiments 1 to 61, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the compound has a terminal half-life, and the terminal half-life is suitable for once-weekly dosing.
65.根据实施方案62至64中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述终末半衰期是在小型猪中测定的,并且是按照本文中“在小型猪中测量终末半衰期的一般方法”所述测得的。65. A compound according to any one of embodiments 62 to 64, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the terminal half-life is determined in miniature pigs and is measured as described in the "General method for measuring terminal half-life in miniature pigs" herein.
66.根据实施方案62至65中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中当在小型猪中测定时,所述终末半衰期为>90小时。66. A compound according to any one of embodiments 62 to 65, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the terminal half-life is >90 hours when measured in minipigs.
67.根据实施方案62至65中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中当在小型猪中测定时,所述终末半衰期为>110小时。67. A compound according to any one of embodiments 62 to 65, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the terminal half-life is >110 hours when measured in minipigs.
68.根据实施方案62至65中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中当在小型猪中测定时,所述终末半衰期为>250小时。68. A compound according to any one of embodiments 62 to 65, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the terminal half-life is >250 hours when measured in minipigs.
69.根据实施方案62至65中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中当在小型猪中测定时,所述终末半衰期为>180小时。69. The compound of any one of embodiments 62 to 65, or a pharmaceutically acceptable salt, ester, or amide thereof, wherein the terminal half-life is >180 hours when measured in minipigs.
70.根据实施方案62至65中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中当在小型猪中测定时,所述终末半衰期为80-240小时。70. The compound of any one of Embodiments 62 to 65, or a pharmaceutically acceptable salt, ester, or amide thereof, wherein the terminal half-life is 80-240 hours when measured in minipigs.
71.根据实施方案62至65中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中当在小型猪中测定时,所述终末半衰期为110-191小时。71. The compound of any one of embodiments 62 to 65, or a pharmaceutically acceptable salt, ester, or amide thereof, wherein the terminal half-life is 110-191 hours when measured in minipigs.
72.药物组合物,其包含根据实施方案1至71中任一项所述的化合物和至少一种药学上可接受的辅料。72. A pharmaceutical composition comprising a compound according to any one of embodiments 1 to 71 and at least one pharmaceutically acceptable excipient.
73.根据实施方案72所述的药物组合物,其中所述药物组合物是液体制剂。73. The pharmaceutical composition of embodiment 72, wherein the pharmaceutical composition is a liquid preparation.
74.根据实施方案72所述的药物组合物,其中所述药物组合物是固体制剂。74. The pharmaceutical composition of embodiment 72, wherein the pharmaceutical composition is a solid dosage form.
75.根据实施方案72所述的药物组合物,其中所述药物组合物用于口服给药。75. A pharmaceutical composition according to embodiment 72, wherein the pharmaceutical composition is for oral administration.
76.根据实施方案74至76中任一项所述的药物组合物,其中所述组合物为片剂形式。76. The pharmaceutical composition of any one of embodiments 74 to 76, wherein the composition is in the form of a tablet.
77.根据实施方案74至77中任一项所述的药物组合物,其中至少一种药学上可接受的辅料是N-(8-(2-羟基苯甲酰基)氨基)辛酸的盐,例如N-(8-(2-羟基苯甲酰基)氨基)辛酸是N-(8-(2-羟基苯甲酰基)氨基)辛酸钠(SNAC)。77. A pharmaceutical composition according to any one of embodiments 74 to 77, wherein at least one pharmaceutically acceptable excipient is a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, for example, N-(8-(2-hydroxybenzoyl)amino)caprylic acid is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC).
78.根据实施方案74至78中任一项所述的药物组合物,其进一步包含润滑剂,如硬脂酸镁。78. The pharmaceutical composition of any one of embodiments 74 to 78, further comprising a lubricant, such as magnesium stearate.
79.片剂,其包含根据实施方案1-71中任一项所述的化合物、N-(8-(2-羟基苯甲酰基)氨基)辛酸的盐、润滑剂和可选的一种或多种药学上可接受的辅料。79. A tablet comprising a compound according to any one of embodiments 1-71, a salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid, a lubricant, and optionally one or more pharmaceutically acceptable excipients.
80.根据实施方案79所述的片剂,其中所述N-(8-(2-羟基苯甲酰基)氨基)辛酸的盐是N-(8-(2-羟基苯甲酰基)氨基)辛酸钠(SNAC)。80. The tablet according to embodiment 79, wherein the salt of N-(8-(2-hydroxybenzoyl)amino)caprylic acid is sodium N-(8-(2-hydroxybenzoyl)amino)caprylate (SNAC).
81.根据实施方案79或实施方案80所述的片剂,其中所述润滑剂是硬脂酸镁。81. The tablet of embodiment 79 or embodiment 80, wherein the lubricant is magnesium stearate.
82.根据实施方案1至71中任一项所述的化合物或根据实施方案72至78中任一项所述的药物组合物或根据实施方案79至81中任一项所述的片剂,其用作药物。82. A compound according to any one of embodiments 1 to 71 or a pharmaceutical composition according to any one of embodiments 72 to 78 or a tablet according to any one of embodiments 79 to 81 for use as a medicament.
83.根据实施方案1至71中任一项所述的化合物或根据实施方案72至78中任一项所述的药物组合物或根据实施方案79至81中任一项所述的片剂,其用于治疗2型糖尿病。83. A compound according to any one of embodiments 1 to 71 or a pharmaceutical composition according to any one of embodiments 72 to 78 or a tablet according to any one of embodiments 79 to 81 for use in the treatment of type 2 diabetes.
84.根据实施方案1至71中任一项所述的化合物或根据实施方案72至78中任一项所述的药物组合物或根据实施方案79至81中任一项所述的片剂,其用于治疗肥胖症。84. A compound according to any one of embodiments 1 to 71 or a pharmaceutical composition according to any one of embodiments 72 to 78 or a tablet according to any one of embodiments 79 to 81 for use in the treatment of obesity.
85.根据实施方案1至71中任一项所述的化合物或根据实施方案72至78中任一项所述的药物组合物或根据实施方案79至81中任一项所述的片剂,其用于治疗肝脏疾病,如肝脂肪变性、非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、肝脏炎症和/或脂肪肝。85. A compound according to any one of embodiments 1 to 71 or a pharmaceutical composition according to any one of embodiments 72 to 78 or a tablet according to any one of embodiments 79 to 81 for use in treating liver diseases such as hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver inflammation and/or fatty liver.
86.根据实施方案1至71中任一项所述的化合物或根据实施方案72至78中任一项所述的药物组合物或根据实施方案79至81中任一项所述的片剂在制备药物中的用途,该药物用于86. Use of a compound according to any one of embodiments 1 to 71, a pharmaceutical composition according to any one of embodiments 72 to 78, or a tablet according to any one of embodiments 79 to 81 in the preparation of a medicament for
a.预防和/或治疗肝脏疾病,如肝脂肪变性、非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、肝脏炎症和/或脂肪肝;a. Prevention and/or treatment of liver diseases such as hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver inflammation and/or fatty liver;
b.预防和/或治疗肥胖症;和/或b. prevention and/or treatment of obesity; and/or
c.预防和/或治疗2型糖尿病。c. Prevention and/or treatment of type 2 diabetes.
87.根据实施方案1至71中任一项所述的化合物或根据实施方案72至78中任一项所述的药物组合物或根据实施方案79至81中任一项所述的片剂在制备用于治疗2型糖尿病的药物中的用途。87. Use of a compound according to any one of embodiments 1 to 71, or a pharmaceutical composition according to any one of embodiments 72 to 78, or a tablet according to any one of embodiments 79 to 81 for the preparation of a medicament for the treatment of type 2 diabetes.
88.根据实施方案1至71中任一项所述的化合物或根据实施方案72至78中任一项所述的药物组合物或根据实施方案79至81中任一项所述的片剂在制备用于治疗肥胖症的药物中的用途。88. Use of a compound according to any one of embodiments 1 to 71, or a pharmaceutical composition according to any one of embodiments 72 to 78, or a tablet according to any one of embodiments 79 to 81 for the preparation of a medicament for the treatment of obesity.
89.预防和/或治疗2型糖尿病的方法,其包括向有需要的受试者施用根据实施方案1至71中任一项所述的化合物或根据实施方案72至78中任一项所述的药物组合物或根据实施方案79至81中任一项所述的片剂。89. A method for preventing and/or treating type 2 diabetes, comprising administering to a subject in need thereof a compound according to any one of Embodiments 1 to 71, a pharmaceutical composition according to any one of Embodiments 72 to 78, or a tablet according to any one of Embodiments 79 to 81.
90.预防和/或治疗肥胖症的方法,其包括向有需要的受试者施用根据实施方案1至71中任一项所述的化合物或根据实施方案72至78中任一项所述的药物组合物或根据实施方案79至81中任一项所述的片剂。90. A method for preventing and/or treating obesity, comprising administering to a subject in need thereof a compound according to any one of Embodiments 1 to 71, a pharmaceutical composition according to any one of Embodiments 72 to 78, or a tablet according to any one of Embodiments 79 to 81.
91.预防和/或治疗肝脏疾病如肝脂肪变性、非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、肝脏炎症和/或脂肪肝的方法,其包括向有需要的受试者施用根据实施方案1至71中任一项所述的化合物或根据实施方案72至78中任一项所述的药物组合物或根据实施方案79至81中任一项所述的片剂。91. A method for preventing and/or treating liver diseases such as hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver inflammation and/or fatty liver, comprising administering to a subject in need thereof a compound according to any one of Embodiments 1 to 71, a pharmaceutical composition according to any one of Embodiments 72 to 78, or a tablet according to any one of Embodiments 79 to 81.
通过以下进一步的非限制性实施方案进一步描述本发明:The present invention is further described by the following further non-limiting embodiments:
1.式I化合物:1. Compounds of formula I:
B-Z(式I)B-Z (Formula I)
或其药学上可接受的盐、酯或酰胺,or a pharmaceutically acceptable salt, ester or amide thereof,
其中Z为GLP-1/GIP受体共激动剂或其衍生物;wherein Z is a GLP-1/GIP receptor co-agonist or a derivative thereof;
其中B为式II的二肽:wherein B is a dipeptide of formula II:
X–Y(式II),X-Y (Formula II),
其中X是通过在X的α-羧酸基团与Y的α-氨基之间形成的酰胺键与Y连接的任何α-氨基酸,wherein X is any α-amino acid linked to Y via an amide bond formed between the α-carboxylic acid group of X and the α-amino group of Y,
其中Y是通过在Y的α-羧酸基团与Z的胺之间形成的酰胺键与Z连接的N-烷基化的α-氨基酸。wherein Y is an N-alkylated α-amino acid linked to Z via an amide bond formed between the α-carboxylic acid group of Y and the amine of Z.
2.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中Y选自肌氨酸、N-仲丁基甘氨酸、脯氨酸、反式-4-羟基脯氨酸、N-甲基谷氨酸、N-甲基正亮氨酸、N-甲基高丙氨酸、N-甲基丙氨酸、N-甲基赖氨酸、N-(2-氨基乙基)甘氨酸、N-己基高丙氨酸、N-丙基丙氨酸、高脯氨酸、N-丙基甘氨酸、N-乙基甘氨酸和N-甲基苯丙氨酸。2. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein Y is selected from sarcosine, N-sec-butylglycine, proline, trans-4-hydroxyproline, N-methylglutamate, N-methylnorleucine, N-methylhomoalanine, N-methylalanine, N-methyllysine, N-(2-aminoethyl)glycine, N-hexylhomoalanine, N-propylalanine, homoproline, N-propylglycine, N-ethylglycine and N-methylphenylalanine.
3.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中X选自赖氨酸、4-氨基苯丙氨酸、D-赖氨酸、丙氨酸、甘氨酸、脯氨酸、D-缬氨酸、高脯氨酸、D-脯氨酸、D-高脯氨酸、D-丙氨酸和氮杂环丁烷-2-羧酸。3. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein X is selected from lysine, 4-aminophenylalanine, D-lysine, alanine, glycine, proline, D-valine, homoproline, D-proline, D-homoproline, D-alanine and azetidine-2-carboxylic acid.
4.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中Y选自肌氨酸、N-仲丁基甘氨酸、脯氨酸、反式-4-羟基脯氨酸、N-甲基谷氨酸、N-甲基正亮氨酸、N-甲基高丙氨酸、N-甲基丙氨酸、N-甲基赖氨酸、N-己基高丙氨酸、N-丙基丙氨酸、高脯氨酸、N-丙基甘氨酸、N-乙基甘氨酸和N-甲基苯丙氨酸。4. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein Y is selected from sarcosine, N-sec-butylglycine, proline, trans-4-hydroxyproline, N-methylglutamate, N-methylnorleucine, N-methylhomoalanine, N-methylalanine, N-methyllysine, N-hexylhomoalanine, N-propylalanine, homoproline, N-propylglycine, N-ethylglycine and N-methylphenylalanine.
5.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中Y为肌氨酸或N-(2-氨基乙基)甘氨酸。5. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein Y is sarcosine or N-(2-aminoethyl)glycine.
6.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中X选自赖氨酸、D-赖氨酸、丙氨酸、亮氨酸、甘氨酸、脯氨酸和天冬氨酸。6. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein X is selected from lysine, D-lysine, alanine, leucine, glycine, proline and aspartic acid.
7.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中X选自赖氨酸、D-赖氨酸和甘氨酸。7. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein X is selected from lysine, D-lysine and glycine.
8.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中二肽能够经历分子内环化以形成2,5-二酮基哌嗪(DKP),使得B与Z之间的酰胺键断裂。8. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the dipeptide is capable of undergoing intramolecular cyclization to form 2,5-diketopiperazine (DKP), resulting in cleavage of the amide bond between B and Z.
9.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述二肽包含取代基b。9. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the dipeptide comprises a substituent b.
10.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述二肽具有取代基b。10. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the dipeptide has a substituent b.
11.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中取代基b任选地通过酰胺键与X共价连接。11. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein substituent b is covalently linked to X, optionally via an amide bond.
12.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述取代基b包含延长体和可选的连接体或由延长体和可选的连接体组成。12. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the substituent b comprises or consists of an extension and an optional linker.
13.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述延长体是化学式1。13. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the elongated body is of Chemical Formula 1.
14.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述取代基b选自化学式16、化学式17、化学式18、化学式19、化学式20、化学式21和化学式22。14. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the substituent b is selected from Formula 16, Formula 17, Formula 18, Formula 19, Formula 20, Formula 21 and Formula 22.
15.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述GLP-1/GIP受体共激动剂的氨基酸序列为YX2EGTX6TSDYSX12X13LX15X16X17AX19X2 0X21FX23X24WLX27X28GX30X31X32X33X34X35X36X37X38X39(SEQ ID NO.:1),其中15. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the amino acid sequence of the GLP-1/GIP receptor co-agonist is YX 2 EGTX 6 TSDYSX 12 X 13 LX 15 X 16 X 17 AX 19 X 2 0 X 21 FX 23 X 24 WLX 27 X 28 GX 30 X 31 X 32 X 33 X 34 X 35 X 36 X 37 X 38 X 39 (SEQ ID NO.: 1), wherein
X2为Aib或A X2 is Aib or A
X6为F或VX 6 is F or V
X12为I或YX 12 is I or Y
X13为Y、A、L、I或Aib X13 is Y, A, L, I or Aib
X15为D或EX 15 is D or E
X16为K或EX 16 is K or E
X17为Q或IX 17 is Q or I
X19为A或QX 19 is A or Q
X20为Q、R、E、H或KX 20 is Q, R, E, H or K
X21为A或EX 21 is A or E
X23为I或V X23 is I or V
X24为E、Q或NX 24 is E, Q or N
X27为L或IX 27 is L or I
X28为A或RX 28 is A or R
X30为G或不存在X 30 is G or does not exist
X31为P或不存在X 31 is P or does not exist
X32为E、S或不存在X 32 is E, S or does not exist
X33为S、K或不存在X 33 is S, K or does not exist
X34为G或不存在X 34 is G or does not exist
X35为A或不存在X 35 is A or does not exist
X36为P或不存在X 36 is P or does not exist
X37为P或不存在X 37 is P or does not exist
X38为P或不存在X 38 is P or does not exist
X39为S或不存在。X 39 is S or absent.
16.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述GLP-1/GIP受体共激动剂的氨基酸序列为16. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the amino acid sequence of the GLP-1/GIP receptor co-agonist is
Y-Aib-EGTFTSDYSIX13LX15X16X17AX19X20X21FX23X24WLX27AGGP SX33GAPPPS(SEQ IDNO.:2),其中 Y - Aib - EGTFTSDYSIX 13 LX 15
X13为L或Aib,X 13 is L or Aib,
X15为D或E,X 15 is D or E,
X16为K或E,X 16 is K or E,
X17为Q或I,X 17 is Q or I,
X19为A或Q,X 19 is A or Q,
X20为R或KX 20 for R or K
X21为A或EX 21 is A or E
X23为I或V X23 is I or V
X24为E或QX 24 is E or Q
X27为L或I;X 27 is L or I;
X33为S或K。X 33 is S or K.
17.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,所述GLP-1/GIP受体共激动剂的氨基酸序列为17. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the amino acid sequence of the GLP-1/GIP receptor co-agonist is
Y-Aib-EGTFTSDYSILLEX16QAAREFIEWLLAGGPSX33GAPPPS(SEQ ID NO.:3),其中Y-Aib-EGTFTSDYSILLEX 16 QAAREFIEWLLAGGPSX 33 GAPPPS (SEQ ID NO.: 3), wherein
X16为K或E,X 16 is K or E,
X33为S或K。X 33 is S or K.
18.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中X16为E且X33为K。18. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein X 16 is E and X 33 is K.
19.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中X16为K且X33为S。19. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein X 16 is K and X 33 is S.
20.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述GLP-1/GIP受体共激动剂的氨基酸序列选自Y-Aib-EGTFTSDYSI-Aib-LDKIAQKAFVQWLIAGGPSSGAPPPS(SEQ ID NO.:4)、20. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the amino acid sequence of the GLP-1/GIP receptor co-agonist is selected from Y-Aib-EGTFTSDYSI-Aib-LDKIAQKAFVQWLIAGGPSSGAPPPS (SEQ ID NO.: 4),
Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPSKGAPPPS(SEQ ID NO.:5)和Y-Aib-EGTFTSDYSILLEKQAAREFIEWLLAGGPSSGAPPPS(SEQ ID NO.:6)。Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPSKGAPPPS (SEQ ID NO.:5) and Y-Aib-EGTFTSDYSILLEKQAAREFIEWLLAGGPSSGAPPPS (SEQ ID NO.:6).
21.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述GLP-1/GIP受体共激动剂包含取代基z,并且其中所述取代基z通过赖氨酸(K)连接至所述GLP-1/GIP受体共激动剂。21. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the GLP-1/GIP receptor co-agonist comprises a substituent z, and wherein the substituent z is linked to the GLP-1/GIP receptor co-agonist via lysine (K).
22.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述取代基z通过位置16、20或33处的赖氨酸(K)连接至所述GLP-1/GIP受体共激动剂。22. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the substituent z is linked to the GLP-1/GIP receptor co-agonist via lysine (K) at position 16, 20 or 33.
23.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述化合物选自第1号化合物、第2号化合物、第3号化合物、第4号化合物、第5号化合物、第6号化合物、第7号化合物、第8号化合物、第9号化合物、第10号化合物、第11号化合物、第12号化合物、第13号化合物、第14号化合物、第15号化合物、第16号化合物、第17号化合物和第18号化合物。23. A compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the compound is selected from Compound No. 1, Compound No. 2, Compound No. 3, Compound No. 4, Compound No. 5, Compound No. 6, Compound No. 7, Compound No. 8, Compound No. 9, Compound No. 10, Compound No. 11, Compound No. 12, Compound No. 13, Compound No. 14, Compound No. 15, Compound No. 16, Compound No. 17 and Compound No. 18.
24.根据前述实施方案中任一项所述的化合物,或其药学上可接受的盐、酯或酰胺,其中所述化合物选自第1、2、3、9和10号化合物。24. The compound according to any one of the preceding embodiments, or a pharmaceutically acceptable salt, ester or amide thereof, wherein the compound is selected from Compound Nos. 1, 2, 3, 9 and 10.
25.药物组合物,其包含根据前述实施方案中任一项所述的化合物和至少一种药学上可接受的辅料。25. A pharmaceutical composition comprising a compound according to any one of the preceding embodiments and at least one pharmaceutically acceptable excipient.
26.根据前述实施方案中任一项所述的药物组合物,其中所述药物组合物是液体制剂。26. The pharmaceutical composition according to any one of the preceding embodiments, wherein the pharmaceutical composition is a liquid formulation.
27.根据前述实施方案中任一项所述的药物组合物,其中所述药物组合物是固体制剂。27. The pharmaceutical composition according to any one of the preceding embodiments, wherein the pharmaceutical composition is a solid preparation.
28.根据前述实施方案中任一项所述的药物组合物,其中所述药物组合物用于口服给药。28. A pharmaceutical composition according to any one of the preceding embodiments, wherein the pharmaceutical composition is for oral administration.
29.根据前述实施方案中任一项所述的药物组合物,其中所述药物组合物用于肠胃外给药。29. The pharmaceutical composition according to any one of the preceding embodiments, wherein the pharmaceutical composition is for parenteral administration.
30.根据前述实施方案中任一项所述的药物组合物,其中所述药物组合物为片剂的形式。30. The pharmaceutical composition according to any one of the preceding embodiments, wherein the pharmaceutical composition is in the form of a tablet.
31.根据前述实施方案中任一项所述的化合物,其用作药物。31. A compound according to any one of the preceding embodiments for use as a medicament.
32.根据前述实施方案中任一项所述的化合物,其用于预防和/或治疗2型糖尿病。32. A compound according to any one of the preceding embodiments for use in the prevention and/or treatment of type 2 diabetes.
33.根据前述实施方案中任一项所述的化合物,其用于预防和/或治疗肥胖症。33. A compound according to any one of the preceding embodiments for use in the prevention and/or treatment of obesity.
34.根据前述实施方案中任一项所述的化合物,其用于预防和/或治疗肝脏疾病,如肝脂肪变性、非酒精性脂肪性肝病(NAFLD)、非酒精性脂肪性肝炎(NASH)、肝脏炎症和/或脂肪肝。34. A compound according to any one of the preceding embodiments, for use in the prevention and/or treatment of liver diseases, such as hepatic steatosis, non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), liver inflammation and/or fatty liver.
实施例Example
该实验部分从缩写列表开始,随后是关于化合物制备的一般方法的部分和关于暴露概况相关性质的测量方法的部分。每个部分中都包括许多具体示例来说明本发明。所有示例化合物均根据本文所述的一般方法来制备。适当时,取代基的化学名称使用AccelrysDraw版本4.1SP1软件和IUPAC命名法来生成。The experimental section begins with a list of abbreviations, followed by a section on general methods for compound preparation and a section on methods for measuring properties related to exposure profiles. A number of specific examples are included in each section to illustrate the present invention. All example compounds are prepared according to the general methods described herein. Where appropriate, the chemical names of substituents are generated using AccelrysDraw version 4.1SP1 software and IUPAC nomenclature.
缩写abbreviation
以下按字母顺序列出的缩写在下文使用:The following abbreviations are used in alphabetical order:
Ado:8-氨基-3,6-二氧杂辛酸Ado: 8-amino-3,6-dioxaoctanoic acid
Aeg:N-(2-氨基乙基)甘氨酸Aeg: N-(2-aminoethyl)glycine
Aib:α-氨基异丁酸Aib: alpha-aminoisobutyric acid
Alloc:烯丙氧羰基Alloc: Allyloxycarbonyl
API:大气压电离API: Atmospheric Pressure Ionization
AUC:曲线下面积AUC: Area Under the Curve
BHK:幼仓鼠肾BHK: Baby Hamster Kidney
Boc:叔丁氧羰基Boc: tert-butyloxycarbonyl
Cl-HOBt:6-氯-1-羟基苯并三唑Cl-HOBt: 6-chloro-1-hydroxybenzotriazole
DCM:二氯甲烷DCM: dichloromethane
DIC:二异丙基碳二亚胺DIC: Diisopropylcarbodiimide
DIPEA:N,N-二异丙基乙胺DIPEA: N,N-diisopropylethylamine
DKP:2,5-二酮基哌嗪DKP: 2,5-diketopiperazine
DMEM:Dulbecco改良Eagle培养基DMEM: Dulbecco's modified Eagle's medium
DPBS:Dulbecco磷酸盐缓冲盐水DPBS: Dulbecco's phosphate buffered saline
EDTA:乙二胺四乙酸EDTA: Ethylenediaminetetraacetic acid
ELISA:酶联免疫吸附测定equiv:摩尔当量ELISA: enzyme-linked immunosorbent assay equiv: molar equivalent
FBS:胎牛血清FBS: Fetal bovine serum
Fmoc:9-芴基甲氧羰基Fmoc: 9-fluorenylmethoxycarbonyl
GIP:葡萄糖依赖性促胰岛素多肽GIP: Glucose-dependent insulinotropic polypeptide
GIPR:葡萄糖依赖性促胰岛素多肽受体GLP-1:胰高血糖素样肽1GLP-1R:胰高血糖素样肽1受体h:小时GIPR: glucose-dependent insulinotropic polypeptide receptor GLP-1: glucagon-like peptide 1 GLP-1R: glucagon-like peptide 1 receptor h: hour
HEPES:4-(2-羟乙基)-1-哌嗪乙磺酸HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid
HFIP:1,1,1,3,3,3-六氟-2-丙醇或六氟异丙醇HPLC:高效液相色谱法HFIP: 1,1,1,3,3,3-hexafluoro-2-propanol or hexafluoroisopropanol HPLC: high performance liquid chromatography
HSA:人血清白蛋白HSA: Human serum albumin
i.v.静脉内i.v. intravenous
LCMS:液相色谱质谱法LCMS: Liquid chromatography mass spectrometry
MeCN:乙腈MeCN: Acetonitrile
MeOH:甲醇MeOH: Methanol
mM:毫摩尔浓度mM: millimolar concentration
mmol:毫摩尔mmol: millimole
min:分钟min: minutes
Mtt:4-甲基三苯甲基Mtt: 4-methyltrityl
NMP:1-甲基-吡咯烷-2-酮NMP: 1-Methyl-2-pyrrolidinone
OtBu:叔丁酯OtBu: tert-butyl ester
Oxyma氰基-羟基亚氨基-乙酸乙酯Oxyma Ethyl cyano-hydroxyiminoacetate
Pbf:2,2,4,6,7-五甲基二氢苯并呋喃-5-磺酰基Pbf: 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl
PBS:磷酸盐缓冲盐水PBS: Phosphate buffered saline
PK:药代动力学PK: Pharmacokinetics
pM:皮摩尔浓度pM: picomolar concentration
P.o.:经口P.o.: Oral
rpm:每分钟转数rpm: revolutions per minute
Rt:保留时间Rt: retention time
Sar:肌氨酸Sar: creatine
s.c.:皮下s.c.: subcutaneous
SNAC:N-[8-(2-羟基苯甲酰基)氨基]辛酸钠SNAC: Sodium N-[8-(2-hydroxybenzoyl)amino]caprylate
SPPS:固相肽合成SPPS: Solid Phase Peptide Synthesis
tBu:叔丁基tBu: tert-butyl
T2D:2型糖尿病T2D: Type 2 diabetes
TFA:三氟乙酸TFA: trifluoroacetic acid
TIS:三异丙基硅烷TIS: Triisopropylsilane
Trt:三苯基甲基或三苯甲基Trt: triphenylmethyl or trityl
UPLC:超高效液相色谱法UPLC: Ultra-Performance Liquid Chromatography
制备本发明化合物的一般方法General Methods for Preparing Compounds of the Invention
下文描述了固相肽合成方法(SPPS法,包括氨基酸脱保护方法,从树脂上切割肽的方法,及其纯化方法),以及检测和表征所得肽的方法(LCMS法)。The following describes a solid phase peptide synthesis method (SPPS method, including a method for amino acid deprotection, a method for cleaving the peptide from the resin, and a method for purification thereof), and a method for detecting and characterizing the resulting peptide (LCMS method).
用于制备C端肽酰胺的树脂是H-Rink Amide-ChemMatrix树脂(例如加载0.5mmol/g)。用于制备C端肽酸的树脂是预加载了适当保护的C端氨基酸衍生物(例如加载0.5mmol/g)的Wang-聚苯乙烯树脂。下述所有操作均在0.1-1.0mmol的合成规模范围内进行。除非另有具体说明,否则使用的Fmoc保护的氨基酸衍生物是推荐的标准:例如由AAPPTEC、Anaspec、Bachem、ChemImpex、Iris Biotech、Midwest Biotech、Gyros ProteinTechnologies或Novabiochem提供的Fmoc-Ala-OH、Fmoc-Arg(Pbf)-OH、Fmoc-Asn(Trt)-OH、Fmoc-Asp(OtBu)-OH、Fmoc-Cys(Trt)-OH、Fmoc-Gln(Trt)-OH、Fmoc-Glu(OtBu)-OH、Fmoc-Gly-OH、Fmoc-His(Trt)-OH、Fmoc-Ile-OH、Fmoc-Leu-OH、Fmoc-Lys(Boc)-OH、Fmoc-Met-OH、Fmoc-Phe-OH、Fmoc-Pro-OH、Fmoc-Ser(tBu)-OH、Fmoc-Thr(tBu)-OH、Fmoc-Trp(Boc)-OH、Fmoc-Tyr(tBu)-OH、Fmoc-Val-OH、Fmoc-Lys(Mtt)-OH、Fmoc-Aib-OH等。在没有其他任何说明时,使用蛋白型的L型氨基酸。为了偶联每种化合物的N端氨基酸,使用了在α-氨基处带有Boc保护的试剂。The resin used to prepare the C-terminal peptide amides was H-Rink Amide-ChemMatrix resin (e.g., loaded at 0.5 mmol/g). The resin used to prepare the C-terminal peptide acids was Wang-polystyrene resin preloaded with appropriately protected C-terminal amino acid derivatives (e.g., loaded at 0.5 mmol/g). All of the following operations were performed in the 0.1-1.0 mmol synthesis scale range. Unless otherwise specified, the Fmoc-protected amino acid derivatives used were the recommended standards: e.g., from AAPPTEC, Anaspec, Bachem, ChemImpex, Iris Biotech, Midwest Biotech, Gyros Biotech, Fmoc-Ala-OH, Fmoc-Arg(Pbf)-OH, Fmoc-Asn(Trt)-OH, Fmoc-Asp(OtBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Gln(Trt)-OH, Fmoc-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-His(Trt) provided by ProteinTechnologies or Novabiochem -OH, Fmoc -Ile-OH, Fmoc-Leu-OH, Fmoc-Lys(Boc)-OH, Fmoc-Met-OH, Fmoc-Phe-OH, Fmoc-Pro-OH, Fmoc-Ser(tBu)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Trp(Boc)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-Val-OH, Fmoc-Lys(Mtt)-OH, Fmoc-Aib-OH, etc. Unless otherwise specified, proteinaceous L-type amino acids were used. To couple the N-terminal amino acid of each compound, a reagent with Boc protection at the α-amino group was used.
在使用SPPS进行二肽附接的情况下,使用以下适当保护的结构单元,例如但不限于Alloc-Aeg(Fmoc)-OH、Boc-Ala-OH、Boc-Asp(OtBu)-OH、Boc-Gly-OH、Boc-Leu-OH、Boc-Lys(Fmoc)-OH、Boc-D-Lys(Fmoc)-OH、Boc-Pro-OH、Fmoc-Aeg(N3)-OH和Fmoc-Sar-OH。在使用SPPS进行取代基附接的情况下,使用以下适当保护的结构单元,例如但不限于Fmoc-8-氨基-3,6-二氧杂辛酸(Fmoc-Ado-OH)、Boc-Lys(Fmoc)-OH、Fmoc-Glu-OtBu、Fmoc-Gly-OH、十六烷二酸单叔丁酯、十八烷二酸单叔丁酯或二十烷二酸单叔丁酯。In the case of dipeptide attachment using SPPS, the following appropriately protected building blocks are used, such as, but not limited to, Alloc-Aeg(Fmoc)-OH, Boc-Ala-OH, Boc-Asp(OtBu)-OH, Boc-Gly-OH, Boc-Leu-OH, Boc-Lys(Fmoc)-OH, Boc-D-Lys(Fmoc)-OH, Boc-Pro-OH, Fmoc-Aeg(N 3 )-OH, and Fmoc-Sar-OH. In the case of substituent attachment using SPPS, the following appropriately protected building blocks are used, such as, but not limited to, Fmoc-8-amino-3,6-dioxaoctanoic acid (Fmoc-Ado-OH), Boc-Lys(Fmoc)-OH, Fmoc-Glu-OtBu, Fmoc-Gly-OH, hexadecanedioic acid mono-tert-butyl ester, octadecanedioic acid mono-tert-butyl ester, or eicosanedioic acid mono-tert-butyl ester.
1.与树脂结合的经保护的肽骨架的合成1. Synthesis of resin-bound protected peptide backbone
万法SPPS_AWanfa SPPS_A
使用制造商提供的方案加以少许修改,在Protein Technologies SymphonyX固相肽合成仪上使用基于Fmoc的化学法进行SPPS。通过不时用氮气鼓泡进行混合。使用以下步骤进行分步组装:1)在DMF中对树脂进行预溶胀;2)通过使用含有或不含1%(v/v)TFA的DMF中的20%(v/v)哌啶进行Fmoc-脱保护,进行两次处理,每次10min;3)用DMF洗涤以除去哌啶;4)通过添加各自3-12equiv的Fmoc-氨基酸、Oxyma和DIC在含有或不含2,4,6-三甲基吡啶的DMF中的溶液,然后混合至少30min,来进行Fmoc-氨基酸的偶联;4)用DMF洗涤以除去过量的试剂;5)在组装完成时用DCM进行最终洗涤。一些氨基酸,例如但不限于空间位阻型氨基酸(例如,Aib)后的氨基酸,被偶联延长的反应时间(例如4h或过夜)以确保反应完成。SPPS was performed using Fmoc-based chemistry on a Protein Technologies SymphonyX solid phase peptide synthesizer using the manufacturer's protocol with minor modifications. Mixing was performed by occasional bubbling with nitrogen. The following steps were used for stepwise assembly: 1) preswelling of the resin in DMF; 2) Fmoc-deprotection by using 20% (v/v) piperidine in DMF with or without 1% (v/v) TFA, two treatments of 10 min each; 3) washing with DMF to remove piperidine; 4) addition of 3-12 equiv of each Fmoc-amino acid, Oxymercaptoethanol, and 1% (v/v) TFA to remove the piperidine; 5) addition of 1% (v/v) Fmoc-amino acid, Oxymercaptoethanol, and 1% (v/v) TFA to remove the piperidine; 6) addition of 1% (v/v) Fmoc-amino acid, Oxymercaptoethanol, and 1% (v/v) TFA to remove the piperidine; 7) addition of 1% (v/v) Fmoc-amino acid, Oxymercaptoethanol, and 1% (v/v) TFA to remove the piperidine; 8) addition of 1% (v/v) Fmoc-amino acid, Oxymercaptoethanol, and 1% (v/v) TFA to remove the piperidine; 9) addition of 1% (v/v) Fmoc-amino acid, Oxymercaptoethanol, and 1% (v/v) TFA to remove the piperidine; 10) and DIC in DMF with or without 2,4,6-collidine, followed by mixing for at least 30 min for coupling of Fmoc-amino acids; 4) washing with DMF to remove excess reagents; 5) final washing with DCM when assembly is complete. Some amino acids, such as but not limited to those following sterically hindered amino acids (e.g., Aib), are coupled with extended reaction times (e.g., 4 h or overnight) to ensure completion of the reaction.
方法:SPPS_BMethod: SPPS_B
使用制造商提供的通用Fmoc方案,在Applied Biosystems 431A固相肽合成仪上使用基于Fmoc的化学法进行SPPS。通过涡旋和不时用氮气鼓泡进行混合。使用以下步骤完成逐步组装:1)通过将各自1O equiv的固体Fmoc-酸溶解在Cl-HOBt在NMP中的1M溶液中,然后添加10equiv的DIC在NMP中的1M溶液,然后与步骤2-3同时混合,以此来活化Fmoc-氨基酸;2)通过使用NMP中的20%(v/v)哌啶处理一次3min,然后第二次处理15min,进行Fmoc脱保护;3)用NMP洗涤以除去哌啶;4)向树脂中加入活化的Fmoc-氨基酸溶液,然后混合至少45min;4)用NMP洗涤以除去过量的试剂;5)在组装完成时用DCM进行最终洗涤。一些氨基酸,例如但不限于空间位阻型氨基酸(例如,Aib)后的氨基酸,被偶联延长的反应时间(例如4h),和/或用新鲜的偶联试剂重复处理,以确保反应完成。SPPS was performed using Fmoc-based chemistry on an Applied Biosystems 431A solid phase peptide synthesizer using the general Fmoc protocol provided by the manufacturer. Mixing was performed by vortexing and occasional bubbling with nitrogen. Stepwise assembly was accomplished using the following steps: 1) Activate the Fmoc-amino acid by dissolving 10 equiv of each solid Fmoc-acid in a 1 M solution of Cl-HOBt in NMP, then adding 10 equiv of a 1 M solution of DIC in NMP, then mixing simultaneously with steps 2-3; 2) Fmoc deprotection was performed by treating once with 20% (v/v) piperidine in NMP for 3 min, then a second time for 15 min; 3) Wash with NMP to remove piperidine; 4) Add the activated Fmoc-amino acid solution to the resin, then mix for at least 45 min; 4) Wash with NMP to remove excess reagent; 5) Final wash with DCM at the completion of assembly. Some amino acids, such as but not limited to the amino acid following a sterically hindered amino acid (eg, Aib), were coupled for extended reaction times (eg, 4 h), and/or repeated treatments with fresh coupling reagents to ensure completion of the reaction.
2.二肽和取代基与同树脂结合的经保护的肽骨架的附接2. Attachment of dipeptides and substituents to the resin-bound protected peptide backbone
方法:DS_AMethod: DS_A
对于含有带有取代基的N端Lys或D-Lys的化合物,使用与SPPS_A中相同的方案继续进行SPPS,以附接二肽B的氨基酸和取代基b的元件。For compounds containing an N-terminal Lys or D-Lys with a substituent, SPPS was continued using the same protocol as in SPPS_A to attach the amino acids of dipeptide B and the elements of substituent b.
方法:DS_BMethod: DS_B
对于在二肽B内含有带有取代基的Aeg的化合物,使用与SPPS_A中相同的方案继续进行SPPS,以附接Fmoc-Aeg(N3)-OH和Nα-Boc保护的N端氨基酸。通过用5-10equiv的三(2-羧基乙基)膦在9:1DMF/水中的溶液处理与树脂结合的肽2-3h,将叠氮基保护基还原为胺。将树脂排干并用9:1DMF/水和DMF洗涤,随后使用与SPPS_A中相同的方案附接取代基b的元件。For compounds containing Aeg with a substituent within dipeptide B, SPPS was continued using the same protocol as in SPPS_A to attach Fmoc-Aeg(N 3 )-OH and the Nα-Boc protected N-terminal amino acid. The azide protecting group was reduced to an amine by treating the resin-bound peptide with 5-10 equiv of tris(2-carboxyethyl)phosphine in 9:1 DMF/water for 2-3 h. The resin was drained and washed with 9:1 DMF/water and DMF, followed by attachment of the element of substituent b using the same protocol as in SPPS_A.
方法:DS_CMethod: DS_C
对于在二肽B内含有带有取代基的Aeg的化合物,作为DS_B的替代方案,使用与SPPS_A中相同的方案继续进行SPPS,以附接Alloc-Aeg(Fmoc)-OH和取代基b的元件。通过在氩气气氛下将与树脂结合的肽用10equiv的硼烷二甲胺复合物和20equiv的吗啉的DMF溶液处理5min,然后添加0.1equiv的钯-四(三苯基膦)的DMF溶液并再处理30min,从而去除Alloc保护基。将树脂排干并用DCM、DMF、MeOH、水和DMF洗涤。然后使用与SPPS_A中相同的方案附接Nα-Boc-保护的N端氨基酸。For compounds containing Aeg with a substituent in dipeptide B, as an alternative to DS_B, SPPS was continued using the same protocol as in SPPS_A to attach the elements of Alloc-Aeg(Fmoc)-OH and substituent b. The Alloc protecting group was removed by treating the resin-bound peptide with 10 equiv of borane dimethylamine complex and 20 equiv of morpholine in DMF under an argon atmosphere for 5 min, followed by the addition of 0.1 equiv of palladium-tetrakis(triphenylphosphine) in DMF and treating for an additional 30 min. The resin was drained and washed with DCM, DMF, MeOH, water, and DMF. The N α -Boc-protected N-terminal amino acid was then attached using the same protocol as in SPPS_A.
方法:DS_DMethod: DS_D
为了附接取代基z,通过用DCM中的30%HFIP洗涤树脂,进行两次处理,每次45min,或用DCM中的80%HFIP洗涤树脂,处理5min、5min、10min、10min、15min、20min和30min,去除带有取代基的Lys的Nε-Mtt保护。将树脂排干并用DCM、DMF、10%DIPEA/DCM、DCM和DMF洗涤。使用与SPPS_A中相同的方案继续进行SPPS,以附接取代基z的元件。To attach the substituent z, the Nε-Mtt protection of the Lys with substituent was removed by washing the resin with 30% HFIP in DCM for two treatments of 45 min each, or with 80% HFIP in DCM for 5 min, 5 min, 10 min, 10 min, 15 min, 20 min, and 30 min. The resin was drained and washed with DCM, DMF, 10% DIPEA/DCM, DCM, and DMF. SPPS was continued using the same protocol as in SPPS_A to attach the element of substituent z.
3.与树脂结合的肽的切割和纯化:3. Cleavage and purification of resin-bound peptides:
方法:CP_AMethod: CP_A
在完成侧链合成后,将肽基树脂用DCM洗涤并干燥,然后用95:2.5:2.5(v/V/v)TFA/水/TIS或92.5:5:2.5(v/V/v)TFA/水/TIS处理2-3h,随后用乙醚沉淀。将沉淀物分离(例如通过过滤或离心),用乙醚洗涤,溶解于合适的溶剂(例如2:1的水/MeCN)中,并静置,直到所有不稳定的加合物均分解。在Phenomenex Luna C8(2)柱(10μm粒径,孔径,250x 21.2mm尺寸)或Phenomenex Gemini-NX C18柱(5μm孔径,孔径,250x50mm尺寸)上,通过反相制备型HPLC进行纯化。使用MeCN在含有0.1%TFA的水中逐渐增加的梯度来完成杂质的分离和产物的洗脱。通过分析型LCMS检查相关级分的身份和纯度。合并含有纯所需产物的级分并冷冻干燥,得到呈白色固体的肽TFA盐。After completion of the side chain synthesis, the peptidyl resin is washed with DCM and dried, then treated with 95:2.5:2.5 (v/v/v) TFA/water/TIS or 92.5:5:2.5 (v/v/v) TFA/water/TIS for 2-3 h, followed by precipitation with ether. The precipitate is isolated (e.g., by filtration or centrifugation), washed with ether, dissolved in a suitable solvent (e.g., 2:1 water/MeCN), and allowed to stand until all unstable adducts are decomposed. The reaction mixture is concentrated on a Phenomenex Luna C8(2) column (10 μm particle size, pore size, 250 x 21.2 mm) or Phenomenex Gemini-NX C18 column (5 μm pore size, Purification was performed by reverse phase preparative HPLC on a 400 μl pore size (250 x 50 mm). Separation of impurities and elution of product was accomplished using a gradually increasing gradient of MeCN in water containing 0.1% TFA. The identity and purity of the relevant fractions were checked by analytical LCMS. The fractions containing the pure desired product were combined and freeze-dried to give the peptide TFA salt as a white solid.
4.从TFA到钠盐的盐交换:4. Salt exchange from TFA to sodium salt:
方法:SX_AMethod: SX_A
将从方法CP_A中分离出的冷冻干燥的肽在适当的水性缓冲液(例如4:1的水/MeCN、0.2M乙酸钠)中溶解至5-20mg/mL,并在必要时用1M NaOH调节至pH 7-8以实现完全溶解。使用Sep-Pak C18柱(0.5-2g)对含肽的缓冲溶液进行盐交换:首先用4倍柱体积的异丙醇,然后用4倍柱体积的MeCN,然后用8倍柱体积的水平衡柱体。将肽溶液加到柱体上,并重新施加流通液以确保肽完全保留。用4倍柱体积的水,然后用10倍柱体积的缓冲溶液(例如pH 7.5)洗涤柱体,该缓冲溶液含有例如但不限于NaHCO3、NaOAc或Na2HPO4。用4倍柱体积的水洗柱,用5-10倍柱体积的50-80%MeCN水溶液洗脱肽。将含肽的洗脱液冷冻干燥,得到呈白色固体的肽钠盐,其原样使用。The freeze-dried peptide isolated from method CP_A is dissolved to 5-20 mg/mL in an appropriate aqueous buffer (e.g., 4:1 water/MeCN, 0.2 M sodium acetate) and adjusted to pH 7-8 with 1 M NaOH if necessary to achieve complete solubility. The peptide-containing buffer solution is salt exchanged using a Sep-Pak C18 column (0.5-2 g): the column is first equilibrated with 4 column volumes of isopropanol, then with 4 column volumes of MeCN, and then with 8 column volumes of water. The peptide solution is added to the column and the flow-through is reapplied to ensure complete retention of the peptide. The column is washed with 4 column volumes of water and then with 10 column volumes of a buffer solution (e.g., pH 7.5) containing, for example, but not limited to, NaHCO 3 , NaOAc, or Na 2 HPO 4 . The column is washed with 4 column volumes of water and the peptide is eluted with 5-10 column volumes of 50-80% MeCN in water. The peptide-containing eluate was freeze-dried to give the peptide sodium salt as a white solid which was used as is.
通用检测和表征方法General Detection and Characterization Methods
LCMS法:LCMS method:
方法:LCMS_AMethod: LCMS_A
通过将适当体积的样品注入到在37℃下平衡的Phenomenex Kinetex C8柱(2.6μm粒径,孔径,4.6x75mm尺寸)上,在Agilent 1260Infinity系列HPLC/MS系统上进行分析。洗脱液A为0.05%TFA水溶液;洗脱液B为9:1MeCN/水中的0.05%TFA。以1.0mL/min的流速,用10min内20-100%洗脱液B的线性梯度实现洗脱。紫外检测设置为214nm。MS电离以API-ES模式和正极性运行,扫描质量范围为500-2000amu。报告每个m/z的最丰富的同位素。The appropriate volume of sample was injected onto a Phenomenex Kinetex C8 column (2.6 μm particle size, The analysis was performed on an Agilent 1260 Infinity Series HPLC/MS system (aperture, 4.6x75 mm size). Eluent A was 0.05% TFA in water; eluent B was 0.05% TFA in 9:1 MeCN/water. Elution was achieved with a linear gradient of 20-100% eluent B in 10 min at a flow rate of 1.0 mL/min. UV detection was set to 214 nm. MS ionization was run in API-ES mode and positive polarity, with a scan mass range of 500-2000 amu. The most abundant isotope for each m/z is reported.
方法:LCMS_BMethod: LCMS_B
通过将适当体积的样品注入到在40℃下平衡的ACQUITY UPLC BEH130柱(1.7μm粒径,孔径,2.1x 150mm尺寸)上,在Waters ACQUITY UPLC/MS系统上进行分析。洗脱液A为0.05%TFA水溶液;洗脱液B为MeCN中的0.05%TFA。用以下梯度和流速实现洗脱:对于紫外检测,在16min内5-95%洗脱液B的线性梯度,流速为0.4mL/min;对于MS检测,在4min内5-60%洗脱液B的线性梯度,流速为0.45mL/min。紫外检测设置为214nm。MS电离以API-ES模式和正极性运行,扫描质量范围为100-2000amu。报告每个m/z的最丰富的同位素。The appropriate volume of sample was injected onto an ACQUITY UPLC BEH130 column (1.7 μm particle size, The samples were analyzed on a Waters ACQUITY UPLC/MS system (aperture, 2.1x 150mm size). Eluent A was 0.05% TFA in water; eluent B was 0.05% TFA in MeCN. Elution was achieved with the following gradient and flow rate: for UV detection, a linear gradient of 5-95% eluent B in 16 min at a flow rate of 0.4 mL/min; for MS detection, a linear gradient of 5-60% eluent B in 4 min at a flow rate of 0.45 mL/min. UV detection was set at 214 nm. MS ionization was run in API-ES mode and positive polarity, with a scan mass range of 100-2000 amu. The most abundant isotope for each m/z is reported.
实施例1:化合物的合成Example 1: Synthesis of compounds
以下使用单字母氨基酸代码描述化合物,Aeg、Aib、D-Lys和Sar除外。每个取代基均包含在它所附接的残基之后的方括号中。The compounds are described below using the single letter amino acid code, with the exception of Aeg, Aib, D-Lys and Sar. Each substituent is contained in square brackets after the residue to which it is attached.
第1号母体化合物Parent compound No. 1
Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[[2-[2-[2-[[(4S)_4-羧基_4-(15-羧基十五碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]-GAPPPS-OHY-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-GAPPPS-OH
SEQ ID NO.:5;取代基:与Lys33附接的化学式8SEQ ID NO.: 5; Substituent: Chemical formula 8 attached to Lys33
合成方法:SPPS_A;DS_D;CP_ASynthesis method: SPPS_A; DS_D; CP_A
计算的分子量(平均值):4901.4DaCalculated molecular weight (average): 4901.4 Da
LCMS_A:Rt=6.3min;实测[M+3H]3+1634.6,[M+4H]4+1226.1LCMS_A: Rt = 6.3 min; found [M+3H] 3+ 1634.6, [M+4H] 4+ 1226.1
第2号母体化合物Parent Compound No. 2
Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[(2S)-2-氨基-6-[[(2S)-2-氨基-6-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]己酰基]氨基]己酰基]-GAPPPS-OHY-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[(2S)-2-amino-6-[[(2S)-2-amino-6-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butanoyl]amino]hexanoyl]amino]hexanoyl]-GAPPPS-OH
SEQ ID NO.:5;取代基:与Lys33附接的化学式10SEQ ID NO.: 5; Substituent: Chemical formula 10 attached to Lys33
合成方法:SPPS_A;DS_D;CP_ASynthesis method: SPPS_A; DS_D; CP_A
计算的分子量(平均值):4867.5DaCalculated molecular weight (average): 4867.5 Da
LCMS_A:Rt=6.1min;实测[M+3H]3+1623.1,[M+4H]4+1217.6LCMS_A: Rt = 6.1 min; found [M+3H] 3+ 1623.1, [M+4H] 4+ 1217.6
第3号母体化合物Parent compound No. 3
Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[(2S)-2-氨基-6-[[(2S)-2-氨基-6-[[(4S)-4-羧基-4-(17-羧基十七碳酰基氨基)丁酰基]氨基]己酰基]氨基]己酰基]-GAPPPS-OHY-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[(2S)-2-amino-6-[[(2S)-2-amino-6-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]hexanoyl]amino]hexanoyl]-GAPPPS-OH
SEQ ID NO.:5;取代基:与Lys33附接的化学式7SEQ ID NO.: 5; Substituent: Chemical Formula 7 attached to Lys33
合成方法:SPPS_A;DS_D;CP_ASynthesis method: SPPS_A; DS_D; CP_A
计算的分子量(平均值):4895.5DaCalculated molecular weight (average): 4895.5 Da
LCMS_A:Rt=6.3min;实测[M+3H]3+1632.4,[M+4H]4+1224.6LCMS_A: Rt = 6.3 min; found [M+3H] 3+ 1632.4, [M+4H] 4+ 1224.6
第4号母体化合物Parent compound No. 4
Y-Aib-EGTFTSDYSILLE-K[(2S)-2-氨基-6-[[(2S)-2-氨基-6-[[(4S)-4-羧基-4-(17-羧基十七碳酰基氨基)丁酰基]氨基]己酰基]氨基]己酰基]-QAAREFIEWLLAGGPSSGAPPPS-OHY-Aib-EGTFTSDYSILLE-K[(2S)-2-amino-6-[[(2S)-2-amino-6-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]hexanoyl]amino]hexanoyl]-QAAREFIEWLLAGGPSSGAPPPS-OH
SEQ ID NO.:6;取代基:与Lys16附接的化学式7SEQ ID NO.: 6; Substituent: Chemical formula 7 attached to Lys16
合成方法:SPPS_A;DS_D;CP_ASynthesis method: SPPS_A; DS_D; CP_A
计算的分子量(平均值):4853.5DaCalculated molecular weight (average): 4853.5 Da
LCMS_A:Rt=5.9min;实测[M+3H]3+1618.5,[M+4H]4+1214.2第5号母体化合物 LCMS_A: Rt=5.9min; Found [M+3H] 3+ 1618.5, [M+4H] 4+ 1214.2 Parent compound No. 5
Y-Aib-EGTFTSDYSI-Aib-LDKIAQK[2-[2-[2-[[2-[2-[2-[[(4S)-4-羧基-4-(19-羧基十九碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]-AFVQWLIAGGPSSGAPPPS-NH2 Y-Aib-EGTFTSDYSI-Aib-LDKIAQK[2-[2-[2-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecaylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-AFVQWLIAGGPSSGAPPPS-NH 2
SEQ ID NO.:4,带有C端酰胺修饰;取代基:与Lys20附接的化学式11SEQ ID NO.: 4, with C-terminal amide modification; Substituent: Chemical formula 11 attached to Lys20
合成方法:SPPS_A;DS_D;CP_ASynthesis method: SPPS_A; DS_D; CP_A
计算的分子量(平均值):4813.5DaLCMS_A:Rt=6.2min;实测[M+3H]3+1605.2,[M+4H]4+1204.3Calculated molecular weight (average): 4813.5 Da LCMS_A: Rt = 6.2 min; Found [M+3H] 3+ 1605.2, [M+4H] 4+ 1204.3
第1号化合物Compound No. 1
(D-Lys)[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]-GAPPPS-OH(D-Lys)[(4S)-4-Carboxy-4-(15-carboxypentadecanoylamino)butyryl]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[2-[2-[2-[[(4S)-4-Carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-GAPPPS-OH
Z:第1号母体化合物;X=D-Lys;Y=Sar;取代基b:与X附接的化学式16;取代基z:与Z的Lys33附接的化学式8。Z: parent compound No. 1; X=D-Lys; Y=Sar; substituent b: chemical formula 16 attached to X; substituent z: chemical formula 8 attached to Lys33 of Z.
合成方法:SPPS_A;DS_A;DS_D;CP_ASynthesis method: SPPS_A; DS_A; DS_D; CP_A
计算的分子量(平均值):5498.2DaLCMS_A:Rt=6.8min;实测[M+3H]3+1833.4,[M+4H]4+1375.3Calculated molecular weight (average): 5498.2 Da LCMS_A: Rt = 6.8 min; Found [M+3H] 3+ 1833.4, [M+4H] 4+ 1375.3
第2号化合物Compound No. 2
G-Aeg[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]-GAPPPS-OHG-Aeg[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-GAPPPS-OH
Z:第1号母体化合物;X=Gly;Y=Aeg;取代基b:与Y附接的化学式16;取代基z:与Z的Lys33附接的化学式8Z: parent compound No. 1; X=Gly; Y=Aeg; substituent b: chemical formula 16 attached to Y; substituent z: chemical formula 8 attached to Lys33 of Z
合成方法:SPPS_B;DS_B;DS_D;CP_ASynthesis method: SPPS_B; DS_B; DS_D; CP_A
计算的分子量(平均值):5456.1DaCalculated molecular weight (average): 5456.1 Da
LCMS_A:Rt=7.0min;实测[M+3H]3+1819.4,[M+4H]4+1364.8第3号化合物 LCMS_A: Rt=7.0min; Found [M+3H] 3+ 1819.4, [M+4H] 4+ 1364.8 Compound No. 3
K[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]-GAPPPS-OHK[(4S)-4-Carboxy-4-(15-carboxypentadecanoylamino)butyryl]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[2-[2-[2-[[(4S)-4-Carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-GAPPPS-OH
Z:第1号母体化合物;X=Lys;Y=Sar;取代基b:与X附接的化学式16;取代基z:与Z的Lys33附接的化学式8Z: parent compound No. 1; X = Lys; Y = Sar; substituent b: chemical formula 16 attached to X; substituent z: chemical formula 8 attached to Lys33 of Z
合成方法:SPPS_A;DS_A;DS_D;CP_ASynthesis method: SPPS_A; DS_A; DS_D; CP_A
计算的分子量(平均值):5498.2DaCalculated molecular weight (average): 5498.2 Da
LCMS_A:Rt=6.9min;实测[M+3H]3+1833.7,[M+4H]4+1375.6LCMS_A: Rt = 6.9 min; found [M+3H] 3+ 1833.7, [M+4H] 4+ 1375.6
第4号化合物Compound No. 4
A-Aeg[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]-GAPPPS-OHA-Aeg[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-GAPPPS-OH
Z:第1号母体化合物;X=Ala;Y=Aeg;取代基b:与Y附接的化学式16;取代基z:与Z的Lys33附接的化学式8Z: parent compound No. 1; X=Ala; Y=Aeg; substituent b: chemical formula 16 attached to Y; substituent z: chemical formula 8 attached to Lys33 of Z
合成方法:SPPS_B;DS_B;DS_D;CP_ASynthesis method: SPPS_B; DS_B; DS_D; CP_A
计算的分子量(平均值):5470.1DaCalculated molecular weight (average): 5470.1 Da
LCMS_A:Rt=7.0min;实测[M+3H]3+1823.8,[M+4H]4+1368.2LCMS_A: Rt = 7.0 min; found [M+3H] 3+ 1823.8, [M+4H] 4+ 1368.2
第5号化合物Compound No. 5
L-Aeg[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]-GAPPPS-OHL-Aeg[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-GAPPPS-OH
Z:第1号母体化合物;X=Leu;Y=Aeg;取代基b:与Y附接的化学式16;取代基z:与Z的Lys33附接的化学式8Z: parent compound No. 1; X = Leu; Y = Aeg; substituent b: chemical formula 16 attached to Y; substituent z: chemical formula 8 attached to Lys33 of Z
合成方法:SPPS_B;DS_B;DS_D;CP_ASynthesis method: SPPS_B; DS_B; DS_D; CP_A
计算的分子量(平均值):5512.2DaCalculated molecular weight (average): 5512.2 Da
LCMS_A:Rt=7.1min;实测[M+3H]3+1838.1,[M+4H]4+1378.9LCMS_A: Rt = 7.1 min; found [M+3H] 3+ 1838.1, [M+4H] 4+ 1378.9
第6号化合物Compound No. 6
P-Aeg[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]-GAPPPS-OHP-Aeg[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-GAPPPS-OH
Z:第1号母体化合物;X=Pro;Y=Aeg;取代基b:与Y附接的化学式16;取代基z:与Z的Lys33附接的化学式8Z: parent compound No. 1; X = Pro; Y = Aeg; substituent b: chemical formula 16 attached to Y; substituent z: chemical formula 8 attached to Lys33 of Z
合成方法:SPPS_B;DS_B;DS_D;CP_ASynthesis method: SPPS_B; DS_B; DS_D; CP_A
计算的分子量(平均值):5496.2DaLCMS_A:Rt=7.0min;实测[M+3H]3+1832.4,[M+4H]4+1374.6Calculated molecular weight (average): 5496.2 Da LCMS_A: Rt = 7.0 min; Found [M+3H] 3+ 1832.4, [M+4H] 4+ 1374.6
第7号化合物Compound No. 7
D-Aeg[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]-GAPPPS-OHD-Aeg[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-GAPPPS-OH
Z:第1号母体化合物;X=Asp;Y=Aeg;取代基b:与Y附接的化学式16;取代基z:与Z的Lys33附接的化学式8Z: parent compound No. 1; X=Asp; Y=Aeg; substituent b: chemical formula 16 attached to Y; substituent z: chemical formula 8 attached to Lys33 of Z
合成方法:SPPS_A;DS_C;DS_D;CP_ASynthesis method: SPPS_A; DS_C; DS_D; CP_A
计算的分子量(平均值):5514.1DaCalculated molecular weight (average): 5514.1 Da
LCMS_B:Rt=10.2min;实测[M+3H]3+1838.8,[M+4H]4+1379.3。LCMS_B: Rt=10.2 min; found [M+3H] 3+ 1838.8, [M+4H] 4+ 1379.3.
第8号化合物Compound No. 8
K[(4S)-4-羧基-4-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]丁酰基]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]-GAPPPS-OHK[(4S)-4-carboxy-4-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]butyryl]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-GAPPPS-OH
Z:第1号母体化合物;X=Lys;Y=Sar;取代基b:与X附接的化学式18;取代基z:与Z的Lys33附接的化学式8Z: parent compound No. 1; X = Lys; Y = Sar; substituent b: chemical formula 18 attached to X; substituent z: chemical formula 8 attached to Lys33 of Z
合成方法:SPPS_B;DS_A;DS_D;CP_ASynthesis method: SPPS_B; DS_A; DS_D; CP_A
计算的分子量(平均值):5627.3DaCalculated molecular weight (average): 5627.3 Da
LCMS_A:Rt=6.9min;实测[M+3H]3+1876.3,[M+4H]4+1407.6第9号化合物 LCMS_A: Rt=6.9min; Found [M+3H] 3+ 1876.3, [M+4H] 4+ 1407.6 Compound No. 9
K[2-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]乙酰基]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]-GAPPPS-OHK[2-[[(4S)-4-Carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]acetyl]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[[2-[2-[[(4S)-4-Carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-GAPPPS-OH
Z:第1号母体化合物;X=Lys;Y=Sar;取代基b:与X附接的化学式19;取代基z:与Z的Lys33附接的化学式8Z: parent compound No. 1; X = Lys; Y = Sar; substituent b: chemical formula 19 attached to X; substituent z: chemical formula 8 attached to Lys33 of Z
合成方法:SPPS_B;DS_A;DS_D;CP_ASynthesis method: SPPS_B; DS_A; DS_D; CP_A
计算的分子量(平均值):5555.2DaLCMS_A:Rt=6.9min;实测[M+3H]3+1852.3,[M+4H]4+1389.7Calculated molecular weight (average): 5555.2 Da LCMS_A: Rt = 6.9 min; Found [M+3H] 3+ 1852.3, [M+4H] 4+ 1389.7
第10号化合物(D-Lys)[2-[2-[2-[[2-[2-[2-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]-GAPPPS-OH Compound No. 10 (D-Lys)[2-[2-[2-[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-GAPPPS-OH
Z:第1号母体化合物;X=D-Lys;Y=Sar;取代基b:与X附接的化学式21;取代基z:与Z的Lys33附接的化学式8Z: parent compound No. 1; X = D-Lys; Y = Sar; substituent b: chemical formula 21 attached to X; substituent z: chemical formula 8 attached to Lys33 of Z
合成方法:SPPS_B;DS_A;DS_D;CP_ASynthesis method: SPPS_B; DS_A; DS_D; CP_A
计算的分子量(平均值):5788.5DaLCMS_A:Rt=6.9min;实测[M+3H]3+1930.3,[M+4H]4+1447.8Calculated molecular weight (average): 5788.5 Da LCMS_A: Rt = 6.9 min; Found [M+3H] 3+ 1930.3, [M+4H] 4+ 1447.8
第11号化合物Compound No. 11
(D-Lys)[(2S)-2-氨基-6-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]己酰(D-Lys)[(2S)-2-amino-6-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]hexanoyl
基]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]-GAPPPS-OH[2-[2-[2-[[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-GAPPPS-OH
Z:第1号母体化合物;X=D-Lys;Y=Sar;取代基b:与X附接的化学式20;取代基z:与Z的Lys33附接的化学式8Z: parent compound No. 1; X = D-Lys; Y = Sar; substituent b: chemical formula 20 attached to X; substituent z: chemical formula 8 attached to Lys33 of Z
合成方法:SPPS_B;DS_A;DS_D;CP_ASynthesis method: SPPS_B; DS_A; DS_D; CP_A
计算的分子量(平均值):5626.4DaCalculated molecular weight (average): 5626.4 Da
LCMS_A:Rt=6.7min;实测[M+3H]3+1876.2,[M+4H]4+1407.2LCMS_A: Rt = 6.7 min; found [M+3H] 3+ 1876.2, [M+4H] 4+ 1407.2
第12号化合物Compound No. 12
K[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰K[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl
基]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[(2S)-2-氨基-6-[[(2S)-2-氨基-6-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]己酰基]氨基]己酰基]-GAPPPS-OH[(2S)-2-amino-6-[[(2S)-2-amino-6-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butanoyl]amino]hexanoyl]amino]hexanoyl]-GAPPPS-OH
Z:第2号母体化合物;X=Lys;Y=Sar;取代基b:与X附接的化学式16;取代基z:与Z的Lys33附接的化学式10Z: parent compound No. 2; X=Lys; Y=Sar; substituent b: chemical formula 16 attached to X; substituent z: chemical formula 10 attached to Lys33 of Z
合成方法:SPPS_A;DS_A;DS_D;CP_ASynthesis method: SPPS_A; DS_A; DS_D; CP_A
计算的分子量(平均值):5464.2DaCalculated molecular weight (average): 5464.2 Da
LCMS_A:Rt=6.6min;实测[M+3H]3+1822.2,[M+4H]4+1366.7LCMS_A: Rt = 6.6 min; found [M+3H] 3+ 1822.2, [M+4H] 4+ 1366.7
第13号化合物Compound No. 13
K[(4S)-4-羧基-4-(17-羧基十七碳酰基氨基)丁酰基]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[(2S)-2-氨基-6-[[(2S)-2-氨基-6-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]己酰基]氨基]己酰基]-GAPPPS-OHK[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyryl]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[(2S)-2-amino-6-[[(2S)-2-amino-6-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]hexanoyl]amino]hexanoyl]-GAPPPS-OH
Z:第2号母体化合物;X=Lys;Y=Sar;取代基b:与X附接的化学式17;取代基z:与Z的Lys33附接的化学式10Z: parent compound No. 2; X = Lys; Y = Sar; substituent b: chemical formula 17 attached to X; substituent z: chemical formula 10 attached to Lys33 of Z
合成方法:SPPS_B;DS_A;DS_D;CP_ASynthesis method: SPPS_B; DS_A; DS_D; CP_A
计算的分子量(平均值):5492.3DaCalculated molecular weight (average): 5492.3 Da
LCMS_A:Rt=6.8min;实测[M+3H]3+1831.4,[M+4H]4+1373.7LCMS_A: Rt = 6.8 min; found [M+3H] 3+ 1831.4, [M+4H] 4+ 1373.7
第14号化合物Compound No. 14
K[(2S)-2,6-双[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]己酰基]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[(2S)-2-氨基-6-[[(2S)-2-氨基-6-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]己酰基]氨基]己酰基]-GAPPPS-OHK[(2S)-2,6-Bis[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]hexanoyl]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[(2S)-2-amino-6-[[(2S)-2-amino-6-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]hexanoyl]amino]hexanoyl]-GAPPPS-OH
Z:第2号母体化合物;X=Lys;Y=Sar;取代基b:与X附接的化学式22;取代基z:与Z的Lys33附接的化学式10Z: parent compound No. 2; X=Lys; Y=Sar; substituent b: chemical formula 22 attached to X; substituent z: chemical formula 10 attached to Lys33 of Z
合成方法:SPPS_A;DS_A;DS_D;CP_ASynthesis method: SPPS_A; DS_A; DS_D; CP_A
计算的分子量(平均值):5989.9DaCalculated molecular weight (average): 5989.9 Da
LCMS_A:Rt=7.0min;实测[M+3H]3+1997.1,[M+4H]4+1498.0LCMS_A: Rt = 7.0 min; found [M+3H] 3+ 1997.1, [M+4H] 4+ 1498.0
第15号化合物Compound No. 15
K[(4S)-4-羧基-4-(17-羧基十七碳酰基氨基)丁酰基]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[(2S)-2-氨基-6-[[(2S)-2-氨基-6-[[(4S)-4-羧基-4-(17-羧基十七碳酰基氨基)丁酰基]氨基]己酰基]氨基]己酰基]-GAPPPS-OHK[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyryl]-Sar-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[(2S)-2-amino-6-[[(2S)-2-amino-6-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyryl]amino]hexanoyl]amino]hexanoyl]-GAPPPS-OH
Z:第3号母体化合物;X=Lys;Y=Sar;取代基b:与X附接的化学式17;取代基z:与Z的Lys33附接的化学式7Z: parent compound No. 3; X = Lys; Y = Sar; substituent b: chemical formula 17 attached to X; substituent z: chemical formula 7 attached to Lys33 of Z
合成方法:SPPS_A;DS_A;DS_D;CP_ASynthesis method: SPPS_A; DS_A; DS_D; CP_A
计算的分子量(平均值):5520.3DaCalculated molecular weight (average): 5520.3 Da
LCMS_A:Rt=7.0min;实测[M+3H]3+1840.9,[M+4H]4+1380.9LCMS_A: Rt = 7.0 min; found [M+3H] 3+ 1840.9, [M+4H] 4+ 1380.9
第16号化合物Compound No. 16
K[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]-Sar-Y-Aib-EGTFTSDYSILLE-K[(2S)-2-氨基-6-[[(2S)-2-氨基-6-[[(4S)-4-羧基-4-(17-羧基十七碳酰基氨基)丁酰基]氨基]己酰基]氨基]己酰基]-QAAREFIEWLLAGGPSSGAPPPS-OHK[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]-Sar-Y-Aib-EGTFTSDYSILLE-K[(2S)-2-amino-6-[[(2S)-2-amino-6-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyryl]amino]hexanoyl]amino]hexanoyl]-QAAREFIEWLLAGGPSSGAPPPS-OH
Z:第4号母体化合物;X=Lys;Y=Sar;取代基b:与X附接的化学式16;取代基z:与Z的Lys16附接的化学式7Z: parent compound No. 4; X = Lys; Y = Sar; substituent b: chemical formula 16 attached to X; substituent z: chemical formula 7 attached to Lys16 of Z
合成方法:SPPS_A;DS_A;DS_D;CP_ASynthesis method: SPPS_A; DS_A; DS_D; CP_A
计算的分子量(平均值):5450.2DaCalculated molecular weight (average): 5450.2 Da
LCMS_A:Rt=6.3min;实测[M+3H]3+1817.3,[M+4H]4+1363.1LCMS_A: Rt = 6.3 min; found [M+3H] 3+ 1817.3, [M+4H] 4+ 1363.1
第17号化合物Compound No. 17
G-Aeg[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]-Y-Aib-EGTFTSDYSILLE-K[(2S)-2-氨基-6-[[(2S)-2-氨基-6-[[(4S)-4-羧基-4-(17-羧基十七碳酰基氨基)丁酰基]氨基]己酰基]氨基]己酰基]-QAAREFIEWLLAGGPSSGAPPPS-OHG-Aeg[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]-Y-Aib-EGTFTSDYSILLE-K[(2S)-2-amino-6-[[(2S)-2-amino-6-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butyryl]amino]hexanoyl]amino]hexanoyl]-QAAREFIEWLLAGGPSSGAPPPS-OH
Z:第4号母体化合物;X=Gly;Y=Aeg;取代基b:与Y附接的化学式16;取代基z:与Z的Lys16附接的化学式7Z: parent compound No. 4; X=Gly; Y=Aeg; substituent b: chemical formula 16 attached to Y; substituent z: chemical formula 7 attached to Lys16 of Z
合成方法:SPPS_A;DS_C;DS_D;CP_ASynthesis method: SPPS_A; DS_C; DS_D; CP_A
计算的分子量(平均值):5408.2DaCalculated molecular weight (average): 5408.2 Da
LCMS_B:Rt=9.5min;实测[M+3H]3+1803.6,[M+4H]4+1353.0第18号化合物 LCMS_B: Rt=9.5min; found [M+3H] 3+ 1803.6, [M+4H] 4+ 1353.0 Compound No. 18
K[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰K[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl
基]-Sar-Y-Aib-EGTFTSDYSI-Aib-LDKIAQK[2-[2-[2-[[2-[2-[2-[[(4S)-4-羧基-4-(19-羧基十九碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]-AFVQWLIAGGPSSGAPPPS-NH2 [2-[2-[2-[2-[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecaylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-AFVQWLIAGGPSSGAPPPS-NH 2
Z:第5号母体化合物;X=Lys;Y=Sar;取代基b:与X附接的化学式16;取代基z:与Z的Lys20附接的化学式11 Z: parent compound No. 5; X = Lys; Y = Sar; substituent b: chemical formula 16 attached to X; substituent z: chemical formula 11 attached to Lys20 of Z
合成方法:SPPS_A;DS_A;DS_D;CP_ASynthesis method: SPPS_A; DS_A; DS_D; CP_A
计算的分子量(平均值):5410.2DaCalculated molecular weight (average): 5410.2 Da
LCMS_A:Rt=6.6min;实测[M+3H]3+1804.0,[M+4H]4+1353.5LCMS_A: Rt = 6.6 min; found [M+3H] 3+ 1804.0, [M+4H] 4+ 1353.5
第1号非转化化合物Non-converting compound No. 1
K[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰K[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl
基]-Val-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[2-[2-[2-[[2-[2-[2-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]-GAPPPS-OH[2-[2-[2-[2-[2-[2-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butanoyl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-GAPPPS-OH
Z:第1号母体化合物;X=Lys;Y=Val;取代基b:与X附接的化学式16;取代基z:与Z的Lys33附接的化学式8Z: parent compound No. 1; X = Lys; Y = Val; substituent b: chemical formula 16 attached to X; substituent z: chemical formula 8 attached to Lys33 of Z
合成方法:SPPS_A;DS_A;DS_D;CP_ASynthesis method: SPPS_A; DS_A; DS_D; CP_A
计算的分子量(平均值):5526.2DaCalculated molecular weight (average): 5526.2 Da
LCMS_A:Rt=6.9min;实测[M+3H]3+1842.8,[M+4H]4+1382.2LCMS_A: Rt = 6.9 min; found [M+3H] 3+ 1842.8, [M+4H] 4+ 1382.2
第2号非转化化合物Non-converting compound No. 2
K[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]-Val-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[(2S)-2-氨基-6-[[(2S)-2-氨基-6-[[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]氨基]己酰基]氨基]己酰基]-GAPPPS-OHK[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]-Val-Y-Aib-EGTFTSDYSILLEEQAAREFIEWLLAGGPS-K[(2S)-2-amino-6-[[(2S)-2-amino-6-[[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]amino]hexanoyl]amino]hexanoyl]-GAPPPS-OH
Z:第2号母体化合物;X=Lys;Y=Val;取代基b:与X附接的化学式16;取代基z:与Z的Lys33附接的化学式10Z: parent compound No. 2; X=Lys; Y=Val; substituent b: chemical formula 16 attached to X; substituent z: chemical formula 10 attached to Lys33 of Z
合成方法:SPPS_A;DS_A;DS_D;CP_ASynthesis method: SPPS_A; DS_A; DS_D; CP_A
计算的分子量(平均值):5492.3DaLCMS_A:Rt=6.6min;实测[M+3H]3+1831.4,[M+4H]4+1373.9Calculated molecular weight (average): 5492.3 Da LCMS_A: Rt = 6.6 min; Found [M+3H] 3+ 1831.4, [M+4H] 4+ 1373.9
第3号非转化化合物Non-converting compound No. 3
K[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰K[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl
基]-Val-Y-Aib-EGTFTSDYSILLE-K[(2S)-2-氨基-6-[[(2S)-2-氨基-6-[[(4S)-4-羧基-4-(17-羧基十七碳酰基氨基)丁酰基]氨基]己酰基]氨基]己酰基]-QAAREFIEWLLAGGPSSGAPPPS-OH[(2S)-2-amino-6-[[(2S)-2-amino-6-[[(4S)-4-carboxy-4-(17-carboxyheptadecanoylamino)butanoyl]amino]hexanoyl]amino]hexanoyl]-QAAREFIEWLLAGGPSSGAPPPS-OH
Z:第4号母体化合物;X=Lys;Y=Val;取代基b:与X附接的化学式16;取代基z:与Z的Lys16附接的化学式7Z: parent compound No. 4; X = Lys; Y = Val; substituent b: chemical formula 16 attached to X; substituent z: chemical formula 7 attached to Lys16 of Z
合成方法:SPPS_A;DS_A;DS_D;CP_ASynthesis method: SPPS_A; DS_A; DS_D; CP_A
计算的分子量(平均值):5478.3DaLCMS_A:Rt=6.1min;实测[M+3H]3+1826.7,[M+4H]4+1370.3Calculated molecular weight (average): 5478.3 Da LCMS_A: Rt = 6.1 min; Found [M+3H] 3+ 1826.7, [M+4H] 4+ 1370.3
第4号非转化化合物Non-converting compound No. 4
K[(4S)-4-羧基-4-(15-羧基十五碳酰基氨基)丁酰基]-Val-Y-Aib-EGTFTSDYSI-Aib-LDKIAQK[2-[2-[2-[[2-[2-[2-[[(4S)-4-羧基-4-(19-羧基十九碳酰基氨基)丁酰基]氨基]乙氧基]乙氧基]乙酰基]氨基]乙氧基]乙氧基]乙酰基]-AFVQWLIAGGPSSGAPPPS-NH2 K[(4S)-4-carboxy-4-(15-carboxypentadecanoylamino)butyryl]-Val-Y-Aib-EGTFTSDYSI-Aib-LDKIAQK[2-[2-[2-[[2-[2-[[(4S)-4-carboxy-4-(19-carboxynonadecanoylamino)butyryl]amino]ethoxy]ethoxy]acetyl]amino]ethoxy]ethoxy]acetyl]-AFVQWLIAGGPSSGAPPPS-NH 2
Z:第5号母体化合物;X=Lys;Y=Val;取代基b:与X附接的化学式16;取代基z:与Z的Lys20附接的化学式11Z: parent compound No. 5; X=Lys; Y=Val; substituent b: chemical formula 16 attached to X; substituent z: chemical formula 11 attached to Lys20 of Z
合成方法:SPPS_A;DS_A;DS_D;CP_ASynthesis method: SPPS_A; DS_A; DS_D; CP_A
计算的分子量(平均值):5438.3DaCalculated molecular weight (average): 5438.3 Da
LCMS_A:Rt=6.6min;实测[M+3H]3+1813.4,[M+4H]4+1360.2LCMS_A: Rt = 6.6 min; found [M+3H] 3+ 1813.4, [M+4H] 4+ 1360.2
测量转化半衰期的一般方法General method for measuring transformation half-life
进行该测定以研究本发明前药的前药到药物的转化半衰期。在37℃孵育后,在体外于pH 7.4下研究转化半衰期。This assay was performed to study the prodrug to drug conversion half-life of the prodrugs of the invention. The conversion half-life was studied in vitro at pH 7.4 after incubation at 37°C.
制剂的制备和取样Preparation and sampling of preparations
将测试化合物溶解于磷酸盐缓冲盐水(140mM NaCl,2.07mM KCl,8.05mM Na2HPO4,1.96mM KH2PO4,pH 7.4)中至浓度为100μM。溶解后测量溶液的pH,必要时用NaOH水溶液调节至pH 7.4。该溶液通过0.22μm注射器过滤器过滤,然后在37℃水浴中孵育。在规定的时间点(例如每24-72小时)取出等份进行LCMS分析。The test compound is dissolved in phosphate buffered saline (140 mM NaCl, 2.07 mM KCl, 8.05 mM Na 2 HPO 4 , 1.96 mM KH 2 PO 4 , pH 7.4) to a concentration of 100 μM. After dissolution, the pH of the solution is measured and adjusted to pH 7.4 with aqueous NaOH if necessary. The solution is filtered through a 0.22 μm syringe filter and then incubated in a 37° C. water bath. Aliquots are removed at specified time points (e.g., every 24-72 hours) for LCMS analysis.
分析与计算Analysis and calculation
使用以上LCMS_A中定义的程序进行LCMS分析。LCMS analysis was performed using the procedure defined in LCMS_A above.
使用214nm处的紫外检测来确定前药、活性药物和DKP的AUC,并计算前药AUC相对于前药加活性药物加DKP的总AUC的比率。绘制该比率的负自然对数随时间的变化图,然后对该关系进行线性回归。从该线性回归计算转化半衰期,即AUC比率=0.5时的时间。The AUC of the prodrug, active drug and DKP were determined using UV detection at 214 nm, and the ratio of the prodrug AUC relative to the total AUC of the prodrug plus active drug plus DKP was calculated. The negative natural logarithm of the ratio was plotted over time, and then a linear regression was performed on the relationship. The conversion half-life, i.e., the time when the AUC ratio = 0.5, was calculated from the linear regression.
实施例2Example 2
本发明化合物的前药到药物的转化半衰期如“测量转化半衰期的一般方法”中所述进行测量。结果呈现在表6中。本发明的化合物具有长得惊人的转化半衰期,其可通过对DKP部分的化学结构的细微修改来调整。The prodrug to drug conversion half-lives of the compounds of the invention were measured as described in "General Methods for Measuring Conversion Half-lives". The results are presented in Table 6. The compounds of the invention have surprisingly long conversion half-lives, which can be adjusted by slight modifications to the chemical structure of the DKP moiety.
表6:前药在pH 7.4和37℃下在PBS缓冲液中的转化半衰期Table 6: Conversion half-life of prodrugs in PBS buffer at pH 7.4 and 37°C
在小型猪中测量终末半衰期的一般方法General method for measuring terminal half-life in miniature pigs
该方法的目的是确定本发明衍生物在静脉内施用于小型猪后的体内半衰期,即它们在体内的时间的延长,因而其作用时间的延长。这在确定所讨论的衍生物的终末半衰期的药代动力学(PK)研究中完成。所谓终末半衰期通常是指在初始分布阶段后测得的,使某种血浆浓度减半所花费的时间长度。The purpose of this method is to determine the in vivo half-life of the derivatives of the invention after intravenous administration to minipigs, i.e. the extension of their time in the body and thus the extension of their duration of action. This is done in a pharmacokinetic (PK) study to determine the terminal half-life of the derivative in question. The so-called terminal half-life usually refers to the length of time it takes for a certain plasma concentration to be reduced by half, measured after the initial distribution phase.
研究Research
在研究中使用的雌性小型猪从EllegaardMinipigs(Dalmose,丹麦)获得,约7-14个月龄,体重约16-35kg。将小型猪单独圈养,并且每天限制饲喂一次SDS小型猪饮食(Special DietsServices,Essex,UK)。Females used in the study Miniature Pigs from Ellegaard Minipigs (Dalmose, Denmark) were obtained at approximately 7-14 months of age and weighed approximately 16-35 kg. Minipigs were housed individually and restricted fed once daily with a SDS minipig diet (Special Diets Services, Essex, UK).
适应环境3周后,将两根永久性中心静脉导管植入每只动物的尾腔静脉中。手术后让动物恢复1周,然后用其进行重复的药代动力学研究,在连续衍生物给药之间具有适当的洗脱期。After 3 weeks of acclimatization, two permanent central venous catheters were implanted in the caudal vena cava of each animal. Animals were allowed to recover for 1 week after surgery and then used for repeated pharmacokinetic studies with appropriate washout periods between consecutive derivative administrations.
动物在给药前禁食大约18小时,并在给药后O至4小时禁食,但在整个时间段内可随意饮水。Animals were fasted for approximately 18 hours prior to dosing and from 0 to 4 hours post-dose, but had free access to water throughout this period.
使用在“制备本发明化合物的一般方法”中的方法SX_A制备实施例1化合物的钠盐。将所得钠盐溶解在含有0.007%聚山梨醇酯20、50mM磷酸钠、70mM氯化钠的pH 7.4缓冲液中至浓度为50-300nmol/mL。通过一根导管静脉内注射化合物(体积对应于通常1-20nmol/kg,例如0.02-0.05mL/kg),并在预定时间点采集血液样品,持续可达给药后21天(优选通过另一根导管)。将血液样品(例如0.8mL)采集到8mM EDTA缓冲液中,然后在4℃下以1942g离心10分钟。The sodium salt of the compound of Example 1 was prepared using method SX_A in the "General Methods for Preparing Compounds of the Invention". The resulting sodium salt was dissolved in a pH 7.4 buffer containing 0.007% polysorbate 20, 50 mM sodium phosphate, 70 mM sodium chloride to a concentration of 50-300 nmol/mL. The compound was injected intravenously through a catheter (volume corresponding to typically 1-20 nmol/kg, e.g., 0.02-0.05 mL/kg), and blood samples were collected at predetermined time points for up to 21 days after administration (preferably through another catheter). Blood samples (e.g., 0.8 mL) were collected in 8 mM EDTA buffer and then centrifuged at 1942 g for 10 minutes at 4°C.
采样与分析Sampling and analysis
将血浆吸移至干冰上的Micronic管中,并保持在-20℃下,直到使用ELISA或类似的基于抗体的测定或LCMS来分析化合物的血浆浓度。通过Phoenix WinNonLin ver.6.4(Pharsight Inc.,Mountain View,CA,USA)中的非房室模型分析各个血浆浓度-时间曲线,并确定所得到的终末半衰期(调和平均值)。The plasma was pipetted into Micronic tubes on dry ice and kept at -20°C until the plasma concentration of the compound was analyzed using ELISA or similar antibody-based assays or LCMS. Each plasma concentration-time curve was analyzed by a non-compartmental model in Phoenix WinNonLin ver. 6.4 (Pharsight Inc., Mountain View, CA, USA), and the resulting terminal half-life (harmonic mean) was determined.
实施例3Example 3
按照本文中“在小型猪中测量终末半衰期的一般方法”所述测得的终末半衰期和/或观察到的终末半衰期在表7中示出。以游离形式施用的第1、2和4号母体化合物具有高得惊人的观察到的终末半衰期,通过添加非转化二肽和取代基(例如,第1号非转化化合物)可进一步延长观察到的终末半衰期。使用转化前药(例如,第1、3、9和10号化合物)导致半衰期比非转化对应物(例如,第1号非转化化合物)更短,因为转化有助于转化前药的消除,但无助于非转化化合物的消除,并且转化无法与其他消除机制区分开来。这提供了前药向母体化合物的转化正在体内发生的证据。由于转化对前药的终末半衰期的贡献,前药的终末半衰期可能比相应的母体化合物更快或更慢。The terminal half-life measured and/or observed as described in the "General Methods for Measuring Terminal Half-Life in Minipigs" herein are shown in Table 7. Parent compounds No. 1, 2, and 4 administered in free form have surprisingly high observed terminal half-lives, which can be further extended by adding non-converting dipeptides and substituents (e.g., non-converting compound No. 1). The use of converting prodrugs (e.g., compounds No. 1, 3, 9, and 10) results in a shorter half-life than the non-converting counterpart (e.g., non-converting compound No. 1) because conversion contributes to the elimination of the converted prodrug, but not to the elimination of the non-converting compound, and conversion cannot be distinguished from other elimination mechanisms. This provides evidence that conversion of the prodrug to the parent compound is occurring in vivo. Due to the contribution of conversion to the terminal half-life of the prodrug, the terminal half-life of the prodrug may be faster or slower than the corresponding parent compound.
表7:小型猪静脉内给药后测得的终末半衰期Table 7: Terminal half-lives measured after intravenous administration in miniature pigs
在比格犬中测量口服生物利用度的一般方法General Methods for Measuring Oral Bioavailability in Beagle Dogs
该方法的目的是确定本发明化合物在经口施用于比格犬后的体内终末半衰期和血浆暴露,即随时间推移到达循环的测试物质的终末半衰期和浓度。这在确定所讨论化合物的这些参数的药代动力学(PK)研究中完成。所谓终末半衰期通常是指在初始分布阶段后测得的,使某种血浆浓度减半所花费的时间长度。The purpose of this method is to determine the terminal half-life and plasma exposure of the compounds of the invention in vivo after oral administration to beagle dogs, i.e. the terminal half-life and concentration of the test substance reaching the circulation over time. This is done in a pharmacokinetic (PK) study to determine these parameters for the compound in question. The so-called terminal half-life usually refers to the length of time it takes for a certain plasma concentration to be halved, measured after the initial distribution phase.
片剂组合物的制备Preparation of tablet compositions
包含从实施例1获得的测试化合物和SNAC(N-(8-(2-羟基苯甲酰基)氨基)辛酸钠)的片剂组合物根据本领域技术人员已知的方法通过将测试物质与辊压的SNAC和硬脂酸镁混合来制备,如例如WO 2019/149880所述。每片由7.7mg硬脂酸镁、2-4mg每种测试化合物和300mg SNAC组成。Tablet compositions comprising the test compound obtained from Example 1 and SNAC (sodium N-(8-(2-hydroxybenzoyl)amino)caprylate) were prepared according to methods known to those skilled in the art by mixing the test substance with roller-compacted SNAC and magnesium stearate, as described, for example, in WO 2019/149880. Each tablet consisted of 7.7 mg of magnesium stearate, 2-4 mg of each test compound and 300 mg of SNAC.
动物、给药和采样Animals, dosing, and sampling
研究中包括在研究期间为1-7岁且体重为9-17kg的雄性比格犬。犬在禁食状态下给药。犬在围栏中分组圈养(12小时光照:12小时黑暗),并单独且限制性地每日一次饲以Royal Canin Medium Adult狗粮(Royal Canin Products,China Branch,或BrogaardenA/S,丹麦)。使用这些犬进行重复的PK研究,其中在连续给药之间具有适当的洗脱期。在开始第一次PK研究之前给予适当的适应期。动物的所有处理、给药和血液采样都由受过训练且熟练的人员进行。在研究之前,令犬禁食整夜以及在给药后0至4小时禁食。在给药前1小时直到给药后4小时限制犬饮水,但在整个期间的其余时间随意饮水。Included in the study are male beagles aged 1-7 years and weighing 9-17 kg during the study. Dogs were administered in a fasted state. Dogs were housed in groups in a fence (12 hours of light: 12 hours of darkness) and fed with Royal Canin Medium Adult dog food (Royal Canin Products, China Branch, or Brogaarden A/S, Denmark) once a day individually and restrictively. Repeated PK studies were performed using these dogs, with an appropriate washout period between consecutive administrations. An appropriate adaptation period was given before starting the first PK study. All treatments, administration, and blood sampling of animals were performed by trained and skilled personnel. Prior to the study, dogs were fasted all night and fasted from 0 to 4 hours after administration. Dogs were restricted from drinking water 1 hour before administration until 4 hours after administration, but were allowed to drink water at will during the rest of the period.
通过向6-8只犬为一组的犬单次经口给药来施用组合物。片剂以下列方式施用:在片剂给药前10min,可以向犬皮下给予大约3nmol/kg的SEQ ID NO.:7(HSQGTFTSDYSKYLDSRRAQDFVQWLMNT),然后将片剂置于犬的口腔后部以防止咀嚼。然后使嘴闭合,并通过注射器或强饲给予10mL自来水,以促进片剂的吞咽。The composition was administered by a single oral administration to dogs in groups of 6-8 dogs. The tablets were administered in the following manner: 10 minutes before tablet administration, approximately 3 nmol/kg of SEQ ID NO.: 7 (HSQGTFTSDYSKYLDSRRAQDFVQWLMNT) may be administered subcutaneously to the dog, and then the tablet was placed in the back of the dog's mouth to prevent chewing. The mouth was then closed and 10 mL of tap water was administered by syringe or gavage to facilitate swallowing of the tablet.
在给药前抽取一份血液样品,并在给药后的预定时间点抽取额外的样品,例如持续长达600小时,以充分覆盖测试物质的完整血浆浓度-时间吸收曲线。对于每个血样时间点,在1.5mL EDTA包被的管中收集大约0.8mL全血,将其轻轻转动以混合样品与EDTA。将血液样品采集到EDTA缓冲液(8mM)中,然后在4℃和2000g下离心10分钟。将血浆吸移至干冰上的Micronic管中,并在-20℃或更低温度下保存直到分析。酌情取得血液样品,例如在前2小时从前腿的头静脉中的venflon取得,随后对于其余的时间点,采用注射器从颈静脉取得。使前几滴从venflon中排出,以避免样品中有来自venflon的肝素盐水。A blood sample is drawn before administration, and additional samples are drawn at predetermined time points after administration, such as for up to 600 hours, to fully cover the complete plasma concentration-time absorption curve of the test substance. For each blood sample time point, approximately 0.8 mL of whole blood is collected in a 1.5 mL EDTA-coated tube, which is gently rotated to mix the sample with EDTA. The blood sample is collected in EDTA buffer (8 mM), then centrifuged at 4 ° C and 2000 g for 10 minutes. Plasma is pipetted into Micronic tubes on dry ice and stored at -20 ° C or lower temperatures until analysis. Blood samples are obtained as appropriate, such as from the venflon in the cephalic vein of the foreleg in the first 2 hours, and then for the remaining time points, a syringe is used to obtain from the jugular vein. The first few drops are discharged from the venflon to avoid heparin saline from the venflon in the sample.
将所有血液样品收集到含有用于稳定的EDTA的试管中,并保存在冰上直至离心。通过离心从全血中分离血浆,并将血浆保存在-20℃或更低温度下直至分析。All blood samples were collected into tubes containing EDTA for stabilization and kept on ice until centrifugation. Plasma was separated from whole blood by centrifugation and stored at -20°C or below until analysis.
分析与计算Analysis and calculation
使用本领域技术人员已知的LC-MS(液相色谱-质谱法)分析血浆的测试物质。该系统由以下任一组成:配备有10阀接口模块TurboFlow系统、CTC HTS PAL自动进样器、Accela1250泵和Hot Pocket柱温箱的Thermo Fisher QExactive质谱仪;或配备有阀接口模块TurboFlow系统、TriPlus RSI自动进样器、Dionex UltiMate 3000泵和Hot Pocket柱温箱的Thermo Fisher QExactive Plus质谱仪。使用1:1乙腈/甲醇在1%甲酸水溶液中的线性梯度实现反相HPLC分离,其中使用以下任一条件:Phenomenex Onyx Monolithic C18柱(50x 2.0mm)和0.8mL/min的流速,30℃;或Agilent Poroshell 120SB-C18柱(50x2.1mm,2.7μm),0.4mL/min的流速,60℃。质谱仪以正电离SIM模式或正电离PRM模式运行。The test substances of plasma were analyzed using LC-MS (liquid chromatography-mass spectrometry) known to those skilled in the art. The system consisted of either: a Thermo Fisher QExactive mass spectrometer equipped with a 10-valve interface module TurboFlow system, a CTC HTS PAL autosampler, an Accela 1250 pump, and a Hot Pocket column thermostat; or a Thermo Fisher QExactive Plus mass spectrometer equipped with a valve interface module TurboFlow system, a TriPlus RSI autosampler, a Dionex UltiMate 3000 pump, and a Hot Pocket column thermostat. Reverse phase HPLC separation was achieved using a linear gradient of 1:1 acetonitrile/methanol in 1% formic acid in water using either a Phenomenex Onyx Monolithic C18 column (50 x 2.0 mm) and a flow rate of 0.8 mL/min at 30° C. or an Agilent Poroshell 120SB-C18 column (50 x 2.1 mm, 2.7 μm) and a flow rate of 0.4 mL/min at 60° C. The mass spectrometer was operated in either positive ionization SIM mode or positive ionization PRM mode.
对于每只个体动物,通过Pharsight Phoenix WinNonLinver.6.4软件或用于PK分析的其他相关软件中的非房室模型分析血浆浓度-时间曲线,并确定所得到的终末半衰期(t1/2)、每剂的最大血浆浓度(Cmax/D)、最大血浆浓度时间(tmax)和每剂至无穷远的曲线下面积(AUC/D)。药代动力学结果的概括统计数据呈现为中值(对于tmax)、调和平均值(t1/2)或算术平均值(Cmax、AUC)。For each individual animal, the plasma concentration-time curve was analyzed by a non-compartmental model in Pharsight Phoenix WinNonLinver.6.4 software or other relevant software for PK analysis, and the resulting terminal half-life (t 1/2 ), maximum plasma concentration of each dose (C max /D), maximum plasma concentration time (t max ) and area under the curve of each dose to infinity (AUC/D) were determined. Summary statistics of pharmacokinetic results were presented as median (for t max ), harmonic mean (t 1/2 ) or arithmetic mean (C max , AUC).
实施例4Example 4
按照本文中“在比格犬中测量口服生物利用度的一般方法”所述测得的药代动力学性质在表8中示出。由于在口服给药后检测到化合物在血浆中的浓度(Cmax/D>0且AUC/D>0),因此所有测试的本发明化合物在该模型中均显示出口服生物利用度。所有测试的化合物也表现出高得惊人的观察到的终末半衰期,如实施例3中所观察到的。The pharmacokinetic properties measured as described in the "General Methods for Measuring Oral Bioavailability in Beagle Dogs" herein are shown in Table 8. Since the concentrations of the compounds in plasma were detected after oral administration ( Cmax /D>0 and AUC/D>0), all tested compounds of the present invention showed oral bioavailability in this model. All tested compounds also showed surprisingly high observed terminal half-lives, as observed in Example 3.
表8:比格犬经口施用后测得的药代动力学参数Table 8: Pharmacokinetic parameters measured after oral administration in beagle dogs
*=三次实验的平均数据* = Average data of three experiments
测量体外功能效力的一般方法General Methods for Measuring Functional Potency in Vitro
本实施例的目的在于测试化合物在体外对人GLP-1和GIP受体的功能活性或效力。体外功能效力是全细胞测定中靶受体活化的量度。如下所述测定实施例1的第1-5号母体化合物的效力。在适当的测定中包括人GLP-1(7-37)(HAEGT FTSDV SSYLE GQAAK EFIAWLVKGR G;SEQ ID NO.:8)和人GIP(YAEGT FISDY SIAMD KIHQQ DFVNW LLAQK GKKND WKHNITQ;SEQ ID NO.:9)作为参考化合物用于比较。The purpose of this example is to test the functional activity or potency of the compounds at human GLP-1 and GIP receptors in vitro. In vitro functional potency is a measure of target receptor activation in a whole cell assay. The potency of the parent compounds No. 1-5 of Example 1 was determined as follows. Human GLP-1 (7-37) (HAEGT FTSDV SSYLE GQAAK EFIAWLVKGR G; SEQ ID NO.: 8) and human GIP (YAEGT FISDY SIAMD KIHQQ DFVNW LLAQK GKKND WKHNITQ; SEQ ID NO.: 9) were included as reference compounds for comparison in the appropriate assays.
原理principle
通过在单独的细胞系中在报告基因测定中测量靶受体的响应来确定体外功能效力。在稳定转染的BHK细胞系中进行该测定,该BHK细胞系表达以下G蛋白偶联受体之一:人GLP-1受体或人GIP受体;并且其中每个细胞系含有与启动子偶联的cAMP响应元件(CRE)DNA以及萤火虫萤光素酶(CRE萤光素酶)基因。当各自的受体被激活时,其导致cAMP的产生,这进而导致萤光素酶蛋白质的表达。当测定孵育完成时,添加萤光素酶底物(萤光素),从而导致萤光素被酶促转化成氧化萤光素并产生生物发光。测量该发光作为该测定的读出。In vitro functional efficacy is determined by measuring the response of the target receptor in a reporter gene assay in a separate cell line. The assay is performed in a stably transfected BHK cell line expressing one of the following G protein-coupled receptors: human GLP-1 receptor or human GIP receptor; and each cell line contains a cAMP response element (CRE) DNA coupled to a promoter and a firefly luciferase (CRE luciferase) gene. When each receptor is activated, it leads to the production of cAMP, which in turn leads to the expression of luciferase protein. When the assay incubation is complete, a luciferase substrate (luciferin) is added, resulting in luciferin being enzymatically converted into oxyluciferin and producing bioluminescence. The luminescence is measured as the readout of the assay.
细胞培养和制备Cell culture and preparation
这些测定中使用的细胞系是以BHKTS13作为亲本细胞系的BHK细胞。该细胞系来源于含有CRE萤光素酶元件的克隆,并且是通过用各自的人受体进一步转染以获得相关细胞系而建立的:BHK CRE luc2PhGLP-1R或BHK CRE luc2P hGIPR。将细胞在细胞培养基中在5% CO2下于37℃培养。将细胞等分并储存在液氮中。使细胞在连续培养中保持,并在每次测定前一天接种。The cell line used in these assays is BHK cells with BHKTS13 as the parental cell line. This cell line is derived from a clone containing the CRE luciferase element and was established by further transfection with the respective human receptor to obtain the relevant cell line: BHK CRE luc2PhGLP-1R or BHK CRE luc2P hGIPR. The cells were cultured in cell culture medium at 37°C under 5% CO2 . The cells were aliquoted and stored in liquid nitrogen. The cells were maintained in continuous culture and seeded the day before each assay.
材料Material
在该测定中使用了以下化学物质:Pluronic F-68 10%(Gibco 2404)、人血清白蛋白(HSA;Sigma A9511)、10%胎牛血清(FBS;Invitrogen16140-071)、鸡蛋清卵白蛋白(Sigma A5503)、不含酚红的DMEM(Gibco21063-029)、DMEM(Gibco 12430-054)、1M Hepes(Gibco 15630)、Glutamax 100x(Gibco 35050)、G418(Invitrogen 10131-027)、潮霉素(Invitrogen 10687-010)和steadylite plus(PerkinElmer 6016757)。The following chemicals were used in the assay: Pluronic F-68 10% (Gibco 2404), human serum albumin (HSA; Sigma A9511), 10% fetal bovine serum (FBS; Invitrogen 16140-071), chicken egg white ovalbumin (Sigma A5503), DMEM without phenol red (Gibco 21063-029), DMEM (Gibco 12430-054), 1M Hepes (Gibco 15630), Glutamax 100x (Gibco 35050), G418 (Invitrogen 10131-027), hygromycin (Invitrogen 10687-010), and steadylite plus (PerkinElmer 6016757).
缓冲液Buffer
GLP-1R细胞培养基由含有10% FBS的DMEM培养基、500μg/mL G418和300μg/mL潮霉素组成。GIPR细胞培养基由含有10% FBS的DMEM培养基、400μg/mL G418和300μg/mL潮霉素组成。测定缓冲液由不含酚红的DMEM、10mM Hepes、1x Glutamax、1%卵白蛋白和0.1%Pluronic F-68组成,其中添加了两倍于最终测定浓度的HSA。将测定缓冲液与等体积的在测定缓冲液中的测试化合物1:1混合,以得到HSA的最终测定浓度。GLP-1R cell culture medium consists of DMEM medium containing 10% FBS, 500 μg/mL G418 and 300 μg/mL hygromycin. GIPR cell culture medium consists of DMEM medium containing 10% FBS, 400 μg/mL G418 and 300 μg/mL hygromycin. Assay buffer consists of DMEM without phenol red, 10 mM Hepes, 1x Glutamax, 1% ovalbumin and 0.1% Pluronic F-68, to which HSA is added at twice the final assay concentration. The assay buffer is mixed 1:1 with an equal volume of the test compound in the assay buffer to obtain a final assay concentration of HSA.
程序program
1)将细胞以5000个细胞/孔进行平板接种,并在测定板中孵育过夜。1) Cells were plated at 5000 cells/well and incubated overnight in assay plates.
2)将细胞在DPBS中洗涤一次。2) Wash cells once in DPBS.
3)将浓度范围为100-300μM的测试化合物和参考化合物的储备液在测定缓冲液中1:150稀释。然后将化合物在96深孔稀释板的第1列中1:10稀释,然后从该行开始,产生3.5倍、12点稀释曲线。3) Stock solutions of test and reference compounds ranging from 100-300 μM were diluted 1: 150 in assay buffer. Compounds were then diluted 1: 10 in column 1 of a 96-deep well dilution plate and then starting from that row, a 3.5-fold, 12-point dilution curve was generated.
4)向测定板的每个孔中添加含有或不含HSA的测定缓冲液(50μl等份)。4) Add assay buffer (50 μl aliquots) with or without HSA to each well of the assay plate.
5)将50μl等份的化合物或空白从稀释板转移至含有测定缓冲液的测定板,该测定缓冲液含有或不含HSA。5) Transfer 50 μl aliquots of compound or blank from the dilution plate to an assay plate containing assay buffer with or without HSA.
6)将测定板在5% CO2培养箱中于37℃孵育3h。6) Incubate the assay plate at 37°C in a 5% CO 2 incubator for 3 h.
7)将细胞用DPBS洗涤一次。7) Wash the cells once with DPBS.
8)向测定板的每个孔添加100μl等份的DPBS。8) Add 100 μl aliquots of DPBS to each well of the assay plate.
9)向测定板的每个孔添加100μl等份的steadylite plus试剂(光敏的)。9) Add 100 μl aliquots of steadylite plus reagent (light sensitive) to each well of the assay plate.
10)将每个测定板用铝箔覆盖以避光,并在室温下以250gm振摇30min。10) Each assay plate was covered with aluminum foil to protect from light and shaken at 250 gm for 30 min at room temperature.
11)在微量滴定板读板仪中读取每个测定板。11) Read each assay plate in a microtiter plate reader.
计算和结果Calculations and Results
来自微量滴定板读板仪的数据首先在Excel中回归,以便根据单个测试化合物的储备浓度和该测定的稀释度计算x轴、对数标尺浓度。然后将该数据传输到GraphPad Prism软件以进行绘图和统计分析。该软件执行非线性回归(log(激动剂)相对于响应)。用该软件计算并以pM为单位报告的EC50值在以下表9中示出。对每个样品最少测量两个重复。所报告的值是重复测量的平均值。在给定条件下,本发明的化合物表现出对人GLP-1R和人GIPR受体的有效功能激活。The data from the microtiter plate reader are first regressed in Excel to calculate the x-axis, logarithmic scale concentration based on the stock concentration of the individual test compounds and the dilution of the assay. The data are then transferred to GraphPad Prism software for plotting and statistical analysis. The software performs nonlinear regression (log (agonist) relative to response). The EC 50 values calculated with the software and reported in pM are shown in Table 9 below. A minimum of two replicates were measured for each sample. The reported values are the average of the replicate measurements. Under given conditions, the compounds of the present invention exhibit effective functional activation of human GLP-1R and human GIPR receptors.
实施例5Example 5
按照本文中“测量体外功能效力的一般方法”所述测得的GLP-1和GIP受体功能效力在表9中示出。在给定条件下,以游离形式施用的母体化合物1-5表现出对人GLP-1受体和人GIP受体的有效功能激活。The GLP-1 and GIP receptor functional potency measured as described herein under "General Methods for Measuring In Vitro Functional Potency" are shown in Table 9. Under the given conditions, parent compounds 1-5 administered in free form exhibited potent functional activation of the human GLP-1 receptor and the human GIP receptor.
表9:在0%和1%HSA的存在下,对人GLP-1R和GIPR的功能效力。Table 9: Functional efficacy at human GLP-1R and GIPR in the presence of 0% and 1% HSA.
nd=未测定。nd = not determined.
虽然本文已经阐述并描述了本发明的某些特征,但是本领域普通技术人员现在将会想到许多修改、替换、改变和等同方案。因此,应当理解,意欲以所附权利要求书涵盖所有这些落入本发明真正范围内的修改和改变。Although certain features of the present invention have been illustrated and described herein, many modifications, substitutions, changes and equivalents will now occur to those skilled in the art. Therefore, it should be understood that the appended claims are intended to cover all such modifications and changes that fall within the true scope of the invention.
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