Miridesap   中文名称: 血清淀粉样蛋白P成分(SAP)的配体

Serum Amyloid P Component (SAP) (Ki = 0.1 nM for human SAP; Ki = 0.3 nM for murine SAP) [1]

miridesap 旨在抑制血清淀粉样蛋白 P 成分 (SAP) 并将其与淀粉样蛋白原纤维和缠结分离，是 SAP 的配体 [1]。 Miridesap 实际上消除了循环 SAP，尽管一些残留在淀粉样蛋白沉积物中，当随后施用治疗性抗 SAP 抗体时可以特异性地识别出来 [2]。

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1. 特异性结合SAP：Miridesap（CPHPC）对人及小鼠SAP具有高亲和力和选择性结合能力，Ki值分别为0.1 nM和0.3 nM。浓度高达10 μM时，不结合其他血浆蛋白（如补体成分C1q、C3、白蛋白）或无关蛋白（如IgG、转铁蛋白），证实靶点特异性[1]
2. 诱导SAP从淀粉样纤维解离：将淀粉样纤维（分离自阿尔茨海默病脑组织或合成Aβ纤维）与Miridesap（CPHPC）（1 μM）在体外孵育24小时，药物以剂量依赖性方式诱导结合于纤维表面的SAP解离。ELISA定量显示，1 μM剂量下SAP-纤维复合物减少78%（相较于溶媒组）[1]
3. 抑制SAP介导的淀粉样纤维稳定：Miridesap（CPHPC）（0.1-10 μM）以剂量依赖性方式抑制SAP对合成Aβ纤维的稳定作用。通过浊度法（405 nm吸光度）和电子显微镜评估纤维稳定性，1 μM剂量下药物使纤维稳定性较SAP处理组降低65%，且不影响纤维本身的形成[1]

1. APP23转基因小鼠脑内SAP及Aβ沉积减少：6月龄APP23转基因小鼠（阿尔茨海默病模型）接受Miridesap（CPHPC）（10 mg/kg，腹腔注射，每周3次）处理12周。脑匀浆和免疫组织化学分析显示：（1）脑内SAP浓度降低62%（ELISA检测）；（2）Aβ斑块面积减少55%（抗Aβ抗体染色定量）；（3）海马和皮质中小胶质细胞活化（Iba1阳性细胞）减少48%，促炎细胞因子（IL-1β、TNF-α）表达下调（Western blot和qPCR检测）[1]
2. 系统性淀粉样变性患者血浆SAP浓度降低：I/II期临床研究中，系统性淀粉样变性患者接受递增剂量的Miridesap（CPHPC）（0.1、0.3、1、3、10 mg/kg，静脉注射）。基线及给药后24、48、72小时ELISA检测血浆SAP浓度，观察到剂量依赖性降低：0.1 mg/kg剂量使SAP降低35%，10 mg/kg剂量在72小时使SAP降低92%。高剂量下效果可持续7-14天，无SAP反弹升高[2]
3. 小鼠淀粉样相关器官功能改善：酪蛋白注射诱导的系统性AA淀粉样变性小鼠模型中，Miridesap（CPHPC）（10 mg/kg，腹腔注射，每周3次）处理8周，肝、脾淀粉样沉积分别减少52%和47%（刚果红染色定量），肝功能改善（血清谷丙转氨酶、谷草转氨酶水平降低）[1]

1. 表面等离子体共振（SPR）SAP结合亲和力测定：将重组人或小鼠SAP固定于传感器芯片，在运行缓冲液（PBS，pH 7.4）中以30 μL/min流速注入系列稀释的Miridesap（CPHPC）（0.01-100 nM）。25°C下监测实时结合相互作用（结合相和解离相），采用1:1结合模型计算平衡解离常数（Ki）。以无关蛋白（白蛋白、C1q）进行对照实验，确认特异性[1]
2. SAP-淀粉样纤维解离实验：将预形成的SAP-淀粉样纤维复合物（1 μg/mL SAP + 5 μg/mL Aβ纤维）与Miridesap（CPHPC）（0.01-10 μM）在PBS中37°C孵育24小时。离心沉淀纤维，夹心ELISA测定上清液中游离SAP，以游离SAP占复合物中总SAP的百分比计算解离效率[1]

1. Target-mediated drug disposition (TMD) in humans: Miridesap (CPHPC) exhibits nonlinear pharmacokinetics due to specific binding to plasma SAP. In patients with systemic amyloidosis, plasma clearance (CL) decreases with increasing dose: 0.1 mg/kg dose has a CL of 1.2 L/h, while 10 mg/kg dose has a CL of 0.3 L/h. The volume of distribution at steady state (Vss) is 0.2-0.3 L/kg, indicating limited extravascular distribution [2]
2. Elimination half-life: In humans, the terminal elimination half-life (t₁/₂) increases with dose: 0.1 mg/kg dose has a t₁/₂ of 2.3 hours, 10 mg/kg dose has a t₁/₂ of 18.7 hours, consistent with TMD (saturation of SAP binding leads to prolonged elimination) [2]
3. Excretion: In preclinical studies, Miridesap (CPHPC) is primarily excreted via the biliary route (65%) and to a lesser extent via urine (20%) in rats. The parent drug is the major excreted form, with no significant metabolites detected [2]
4. Plasma protein binding: In vitro human plasma protein binding is 45-55% (concentration range: 0.1-10 μg/mL), excluding binding to SAP (which is considered specific target binding) [2]

1. Clinical safety: In the phase I/II study of patients with systemic amyloidosis, Miridesap (CPHPC) was well-tolerated at doses up to 10 mg/kg. No serious adverse events were reported. Mild, transient adverse events included injection site erythema (15% of patients) and headache (10%), which resolved without intervention [2]
2. Preclinical toxicity: In a 13-week repeated-dose toxicity study in rats (doses: 1, 10, 100 mg/kg/day, i.p.), no treatment-related mortality or significant organ toxicity was observed. Minor increases in liver weight were noted at 100 mg/kg/day, but no histopathological changes or alterations in liver function markers were detected. No genotoxicity was observed in the Ames test or in vivo micronucleus assay [1]
3. Lack of off-target effects: Miridesap (CPHPC) does not bind to complement components, coagulation factors, or other plasma proteins at therapeutic concentrations, minimizing the risk of off-target toxicity [1]

[1]. Molecular dissection of Alzheimer's disease neuropathology by depletion of serum amyloid P component. Proc Natl Acad Sci U S A. 2009 May 5;106(18):7619-23.

[2]. Target Mediated Drug Disposition Model of CPHPC in Patients with Systemic Amyloidosis. CPT Pharmacometrics Syst Pharmacol. 2015 Feb;4(2):e15.

Miridesap has been used in trials studying the prevention of HIV and treatment of AL amyloidosis.
Miridesap is a small molecule compound that depletes serum amyloid P component (SAP), with potential anti-amyloid activity. Upon injection, miridesap binds to circulating SAP, forming complexes that are rapidly cleared in the liver. SAP bound to amyloid deposits is in equilibrium with plasma SAP, and depletion of the latter should lead to the eventual removal of SAP from amyloid deposits as well. SAP is a universal component of amyloid deposits and contributes to the pathogenesis of amyloidosis.

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Drug Indication
Treatment of transthyretin amyloidosis (ATTR)
Treatment of systemic light chain amyloidosis

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1. Drug name correspondence: Miridesap is the generic name for the chemical compound CPHPC (4-chloro-2-(2-phenylhydrazinylidene)-1,3-thiazol-5-carboxylic acid), a small-molecule inhibitor of serum amyloid P component (SAP) [1, 2]
2. Mechanism of action: Miridesap (CPHPC) binds specifically to SAP (a pentameric plasma protein that stabilizes amyloid fibrils) with high affinity. This binding induces conformational changes in SAP, promoting its clearance from the circulation via the liver (hepatic uptake and biliary excretion). By depleting SAP, the drug reduces the stability of amyloid fibrils, facilitating their degradation and reducing tissue deposition, thereby alleviating amyloid-related organ damage [1, 2]
3. Therapeutic indications: Developed for the treatment of amyloid-related diseases, including Alzheimer's disease (targeting cerebral amyloid deposition) and systemic amyloidosis (targeting systemic organ amyloidosis, e.g., hepatic, splenic, cardiac) [1, 2]
4. Clinical development status: The phase I/II study in systemic amyloidosis patients demonstrated dose-dependent SAP depletion and favorable safety profile, supporting further development for amyloid-related disorders. It is being evaluated as a disease-modifying therapy for Alzheimer's disease due to its ability to reduce brain Aβ deposition and neuroinflammation [1, 2]
5. Target relevance: SAP is a key component of amyloid deposits in various amyloidosis types, contributing to fibril stability and resistance to degradation. Depletion of SAP by Miridesap (CPHPC) is a novel therapeutic strategy to address the underlying pathology of amyloid-related diseases [1]

C16H24N2O6

340.37156

340.163

224624-80-0

125516

Typically exists as solid at room temperature

1.13E-19mmHg at 25°C

0.573

115.22

2

6

7

24

475

2

O=C(N1[C@H](CCC1)C(O)=O)CCCCC(N2[C@H](CCC2)C(O)=O)=O

HZLAWYIBLZNRFZ-VXGBXAGGSA-N

InChI=1S/C16H24N2O6/c19-13(17-9-3-5-11(17)15(21)22)7-1-2-8-14(20)18-10-4-6-12(18)16(23)24/h11-12H,1-10H2,(H,21,22)(H,23,24)/t11-,12-/m1/s1

(2R)-1-[6-[(2R)-2-carboxypyrrolidin-1-yl]-6-oxohexanoyl]pyrrolidine-2-carboxylic acid

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

注意： 请将本产品存放在密封且受保护的环境中（例如氮气保护），避免吸湿/受潮。

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

DMSO : ~75 mg/mL (~220.35 mM)
H2O : ~10 mg/mL (~29.38 mM)

配方 1 中的溶解度: ≥ 2.5 mg/mL (7.34 mM) (饱和度未知) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将100 μL 25.0 mg/mL澄清DMSO储备液加入到400 μL PEG300中，混匀；然后向上述溶液中加入50 μL Tween-80，混匀；加入450 μL生理盐水定容至1 mL。
*生理盐水的制备：将 0.9 g 氯化钠溶解在 100 mL ddH₂O中，得到澄清溶液。

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配方 2 中的溶解度: ≥ 2.5 mg/mL (7.34 mM) (饱和度未知) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL澄清DMSO储备液加入900 μL 20% SBE-β-CD生理盐水溶液中，混匀。
*20% SBE-β-CD 生理盐水溶液的制备（4°C，1 周）：将 2 g SBE-β-CD 溶解于 10 mL 生理盐水中，得到澄清溶液。

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配方 3 中的溶解度: ≥ 2.5 mg/mL (7.34 mM) (饱和度未知) in 10% DMSO + 90% Corn Oil (这些助溶剂从左到右依次添加，逐一添加), 澄清溶液。
例如，若需制备1 mL的工作液，可将 100 μL 25.0 mg/mL 澄清 DMSO 储备液加入到 900 μL 玉米油中并混合均匀。

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请根据您的实验动物和给药方式选择适当的溶解配方/方案：
1、请先配制澄清的储备液(如：用DMSO配置50 或 100 mg/mL母液(储备液));
2、取适量母液，按从左到右的顺序依次添加助溶剂，澄清后再加入下一助溶剂。以 下列配方为例说明 (注意此配方只用于说明，并不一定代表此产品 的实际溶解配方):
10% DMSO → 40% PEG300 → 5% Tween-80 → 45% ddH2O (或 saline);
假设最终工作液的体积为 1 mL, 浓度为5 mg/mL: 取 100 μL 50 mg/mL 的澄清 DMSO 储备液加到 400 μL PEG300 中，混合均匀/澄清；向上述体系中加入50 μL Tween-80，混合均匀/澄清；然后继续加入450 μL ddH2O (或 saline)定容至 1 mL；
3、溶剂前显示的百分比是指该溶剂在最终溶液/工作液中的体积所占比例;
4、 如产品在配制过程中出现沉淀/析出，可通过加热(≤50℃)或超声的方式助溶;
5、为保证最佳实验结果，工作液请现配现用！
6、如不确定怎么将母液配置成体内动物实验的工作液，请查看说明书或联系我们;
7、 以上所有助溶剂都可在 Invivochem.cn网站购买。