zilucoplan（RA101495；1-1000 nM；30 分钟）的 IC50 值为 474.5 pM，可抑制脂多糖引起的人全血中 C5a 血浆水平的增加。当 zilucoplan 以 1 nM 浓度使用时，C5a 血浆水平降低 65.7% [2]。通过防止 C5 被 C5 转化酶分解为 C5a 和 C5b 并附着到预先形成的 C5b 以在空间上阻断与 C6 的相互作用，zilucoplan 与补体成分 5 (C5) 结合并防止膜攻击复合物的下游组装（MAC；C5b- 9）[1]。

在用人补体治疗的 C5 缺陷小鼠中，zilucoplan（RA101495；10 mg/kg；SC；每天，持续 6 天）可抑制免疫介导的坏死性肌病 (IMNM) 的发展[1]。在 C57BL/6 小鼠中，zilucoplan（10 mg/kg；皮下注射；每天一次，持续 6 天）显示出对预防肌病的保护作用[1]。

Animal/Disease Models: C57BL/10SnJ C5-deficient (C5def) mice with anti-HMGCR+ IMNM IgG xenografts[1]
Doses: 10 mg/kg
Route of Administration: subcutaneous (sc) injection; daily, for 6 days
Experimental Results: Prevented muscle strength loss in C5def mice with less complement deposition on myofibres and consequently less necrosis/regeneration.

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Animal/Disease Models: C57BL/6 mice with anti-HMGCR+ IMNM IgG xenografts[1]
Doses: 10 mg/kg
Route of Administration: subcutaneous (sc) injection; daily, for 6 days
Experimental Results: Prevented muscle weakness and decreased regenerated myofibres. diminished necrotic cells as well as regenerating cells expressing foetal myosin.

Absorption, Distribution and Excretion
Following single and multiple daily subcutaneous administration of 0.3 mg/kg zilucoplan, time to reach peak plasma concentrations (Tmax) ranged from three to six hours. Following daily subcutaneous dosing of 0.3 mg/kg zilucoplan for 14 days in healthy subjects, both the peak plasma concentration and exposure (AUCtau) increased by approximately 3-fold. After daily repeated subcutaneous administration of 0.3 mg/kg zilucoplan, plasma concentrations of zilucoplan were consistent, with steady state trough concentrations being reached by four weeks of treatment with zilucoplan through 12 weeks.
Less than 1% of zilucoplan and its metabolites are excreted in urine and feces.
The mean volume of distribution at steady state was 3.51 L in the population pharmacokinetics analysis for adult patients with gMG.
No information is available.

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Metabolism / Metabolites
Zilucoplan is expected to be degraded into small peptides and amino acids via catabolic pathways. RA103488 and RA102758 are two major metabolites detected in plasma. RA103488 is formed by CYP4F2-mediated metabolism and has comparable pharmacological activity to its parent compound; however, since RA103488 is present at much lower concentrations compared to zilucoplan, its contribution to the pharmacological action of zilucoplan is expected to be low. RA102758, formed by protease-mediated degradation, is pharmacologically inactive. The AUCs of both metabolites were approximately 10% of the parent AUC.

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Biological Half-Life
The mean plasma terminal half-life of zilucoplan was approximately 172 hours (7 to 8 days).

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
Zilucoplan is expected to be degraded into small peptides and amino acids via catabolic pathways in the maternal circulation and infant gastrointestinal tract. It is unlikely to be absorbed by the breastfed infant or adversely affect the infant. No special precautions are required.
◉ Effects in Breastfed Infants
Relevant published information was not found as of the revision date.
◉ Effects on Lactation and Breastmilk
Relevant published information was not found as of the revision date.

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Protein Binding
Zilucoplan and its two major metabolites, RA103488 and RA102758, are more than 99% bound to plasma proteins.

[1]. Prevention of Anti-HMGCR Immune-Mediated Necrotising Myopathy by C5 Complement Inhibition in a Humanised Mouse Model. Biomedicines. 2022 Aug 20;10(8):2036.

[2]. Chemical synthesis and characterisation of the complement C5 inhibitory peptide zilucoplan. Amino Acids. 2021 Jan;53(1):143-147.

Zilucoplan is a 15 amino-acid, synthetic macrocyclic peptide with formula C172H278N24O55. Its sodium salt is used for the treatment of generalised myasthenia gravis (a disease that leads to muscle weakness and tiredness) in adults whose immune system produces antibodies against acetylcholine receptors. It has a role as a complement component 5 inhibitor and an immunosuppressive agent. It is a macrocycle, a homodetic cyclic peptide and a polyether. It is a conjugate acid of a zilucoplan(4-).
Zilucoplan is a 15 amino-acid, synthetic macrocyclic peptide. It is a complement inhibitor that works to prevent the activation of C5, which is a complement protein involved in the innate immune system to initiate inflammatory responses. On October 17, 2023, zilucoplan gained its first FDA approval for the treatment of generalized myasthenia gravis. It was also later approved by the EMA on December 4, 2023, as an add-on treatment for the same condition.
Zilucoplan is a Complement Inhibitor. The mechanism of action of zilucoplan is as a Complement Inhibitor.
Zilucoplan is a synthetic macrocyclic peptide inhibitor of the terminal complement protein C5, with potential anti-inflammatory and cell protective activities. Upon subcutaneous administration, complement zilucoplan binds to a unique site in terminal complement protein C5, which blocks C5 cleavage into C5a and C5b and prevents the C5b-dependent assembly of the membrane-attack complex (MAC). Zilucoplan also inhibits the interaction between C5b and C6, thereby further blocking MAC assembly. This prevents MAC-mediated lysis and destruction of red blood cells (RBCs) that occurs in complement-mediated diseases, such as paroxysmal nocturnal hemoglobinuria (PNH), generalized myasthenia gravis (gMG) and lupus nephritis (LN). C5, a complement pathway protein, is expressed at high levels by the liver.

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Drug Indication
Zilucoplan is indicated as the main treatment or add-on treatment to standard therapy for generalized myasthenia gravis (gMG) in adult patients who are anti-acetylcholine receptor (AChR) antibody-positive by the FDA and EMA respectively.
Treatment of myasthenia gravis

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Mechanism of Action
The complement system is part of the innate immune system and is critical in inflammatory reactions in response to pathogenic bacteria. Activation pathways of the complement system involve the cleavage of the complement protein C5 by C5 convertases to form C5a, a potent anaphylatoxin, and C5b. Cleavage of C5 also recruits C6, C7, C8, and C9. C5b binds to C6 to yield the terminal complement complex C5b9, a hydrophilic pore that spans the cell membrane. C5b9 causes an influx of water and ions, resulting in osmotic lysis of the targeted cell. The terminal complement cascade has been implicated in the pathophysiology of various inflammatory and autoimmune disorders, including gMG. gMG is an autoimmune disorder characterized by pathogenic autoantibodies that bind to AChRs. Accumulated MAC on the postsynaptic plasma membrane of the neuromuscular junction leads to muscle weakness and damage. The exact mechanism of zilucoplan in gMG has not been fully elucidated. Zilucoplan binds to the complement protein C5 with high affinity to inhibit its cleavage to C5a and C5b, preventing the generation of C5b9.

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Pharmacodynamics
In clinical trials consisting of anti-AChR antibody-positive adults with gMG, zilucoplan improved the signs and symptoms of myasthenia gravis, including muscle weakness. In vitro, it blocked the activation of C5 clinical variants. Zilucoplan causes complement inhibition in a dose-dependent manner: In clinical trials, complement inhibition of 97.5% by zilucoplan was observed by the end of the first week and persisted throughout the 12-week treatment period.

C172H278N24O55

3562.17557096481

3560.972

1841136-73-9

Zilucoplan TFA

133083018

White to off-white solid powder

4.8

1070

28

57

142

251

6980

16

O=C([C@H](C1CCCCC1)NC([C@@H]1CCCN1C([C@H](CC1C=CC(=CC=1)O)NC([C@H](CCC(=O)O)NC([C@H](CC1=CNC2C1=CC=CN=2)NC([C@H](CC1C=CC(=CC=1)O)NC([C@H](C(C)(C)C)NC([C@H](CC(=O)O)N(C)C([C@@H]1CC(NCCCC[C@@H](C(N[C@H](C(N[C@@H](CCC(=O)O)C(N[C@@H](CCCNC(=N)N)C(N[C@@H](CC2C=CC=CC=2)C(N1)=O)=O)=O)=O)C(C)C)=O)NC(C)=O)=O)=O)=O)=O)=O)=O)=O)=O)=O)N[C@H](C(=O)O)CCCCNC(CCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCOCCNC(CC[C@@H](C(=O)O)NC(CCCCCCCCCCCCCCC)=O)=O)=O

JDXCOXKBIGBZSK-PSNKNOTQSA-N

InChI=1S/C172H278N24O55/c1-9-10-11-12-13-14-15-16-17-18-19-20-27-44-146(202)182-136(170(226)227)53-56-144(200)177-64-67-229-69-71-231-73-75-233-77-79-235-81-83-237-85-87-239-89-91-241-93-95-243-97-99-245-101-103-247-105-107-249-109-111-251-113-112-250-110-108-248-106-104-246-102-100-244-98-96-242-94-92-240-90-88-238-86-84-236-82-80-234-78-76-232-74-72-230-70-68-228-66-59-145(201)175-60-31-29-41-135(169(224)225)186-165(220)152(126-37-25-22-26-38-126)193-162(217)142-43-34-65-196(142)168(223)140(116-125-47-51-129(199)52-48-125)190-157(212)133(54-57-148(204)205)184-161(216)139(117-127-120-180-154-130(127)39-32-62-178-154)188-159(214)138(115-124-45-49-128(198)50-46-124)189-166(221)153(172(5,6)7)194-163(218)143(119-150(208)209)195(8)167(222)141-118-147(203)176-61-30-28-40-131(181-122(4)197)158(213)192-151(121(2)3)164(219)185-134(55-58-149(206)207)156(211)183-132(42-33-63-179-171(173)174)155(210)187-137(160(215)191-141)114-123-35-23-21-24-36-123/h21,23-24,32,35-36,39,45-52,62,120-121,126,131-143,151-153,198-199H,9-20,22,25-31,33-34,37-38,40-44,53-61,63-119H2,1-8H3,(H,175,201)(H,176,203)(H,177,200)(H,178,180)(H,181,197)(H,182,202)(H,183,211)(H,184,216)(H,185,219)(H,186,220)(H,187,210)(H,188,214)(H,189,221)(H,190,212)(H,191,215)(H,192,213)(H,193,217)(H,194,218)(H,204,205)(H,206,207)(H,208,209)(H,224,225)(H,226,227)(H4,173,174,179)/t131-,132-,133-,134-,135-,136-,137-,138-,139-,140-,141-,142-,143-,151-,152-,153+/m0/s1

(2S)-2-[[(2S)-2-[[(2S)-1-[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S)-2-[[(2S,5S,8S,11S,14S,22S)-22-acetamido-11-benzyl-8-(3-carbamimidamidopropyl)-5-(2-carboxyethyl)-3,6,9,12,16,23-hexaoxo-2-propan-2-yl-1,4,7,10,13,17-hexazacyclotricosane-14-carbonyl]-methylamino]-3-carboxypropanoyl]amino]-3,3-dimethylbutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]amino]-3-(1H-pyrrolo[2,3-b]pyridin-3-yl)propanoyl]amino]-4-carboxybutanoyl]amino]-3-(4-hydroxyphenyl)propanoyl]pyrrolidine-2-carbonyl]amino]-2-cyclohexylacetyl]amino]-6-[3-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[2-[[(4S)-4-carboxy-4-(hexadecanoylamino)butanoyl]amino]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propanoylamino]hexanoic acid

Zilbrysq

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，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)

May dissolve in DMSO (in most cases), if not, try other solvents such as H2O, Ethanol, or DMF with a minute amount of products to avoid loss of samples

注意: 如下所列的是一些常用的体内动物实验溶解配方，主要用于溶解难溶或不溶于水的产品（水溶度<1 mg/mL）。 建议您先取少量样品进行尝试，如该配方可行，再根据实验需求增加样品量。

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注射用配方1: DMSO : Tween 80： Saline = 10 : 5 : 85 (如： 100 μL DMSO → 50 μL Tween 80 → 850 μL Saline)
*生理盐水/Saline的制备：将0.9g氯化钠/NaCl溶解在100 mL ddH ₂ O中，得到澄清溶液。
注射用配方 2: DMSO : PEG300 ：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL DMSO → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)
注射用配方 3: DMSO : Corn oil = 10 : 90 (如： 100 μL DMSO → 900 μL Corn oil)
示例: 以注射用配方 3 (DMSO : Corn oil = 10 : 90) 为例说明, 如果要配制 1 mL 2.5 mg/mL的工作液, 您可以取 100 μL 25 mg/mL 澄清的 DMSO 储备液，加到 900 μL Corn oil/玉米油中, 混合均匀。

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注射用配方 4: DMSO : 20% SBE-β-CD in Saline = 10 : 90 [如：100 μL DMSO → 900 μL (20% SBE-β-CD in Saline)]
*20% SBE-β-CD in Saline的制备（4°C，储存1周）：将2g SBE-β-CD (磺丁基-β-环糊精) 溶解于10mL生理盐水中，得到澄清溶液。
注射用配方 5: 2-Hydroxypropyl-β-cyclodextrin : Saline = 50 : 50 (如： 500 μL 2-Hydroxypropyl-β-cyclodextrin (羟丙基环胡精)→ 500 μL Saline)
注射用配方 6: DMSO : PEG300 : Castor oil : Saline = 5 : 10 : 20 : 65 (如： 50 μL DMSO → 100 μL PEG300 → 200 μL Castor oil → 650 μL Saline)
注射用配方 7: Ethanol : Cremophor : Saline = 10： 10 : 80 (如： 100 μL Ethanol → 100 μL Cremophor → 800 μL Saline)
注射用配方 8: 溶解于Cremophor/Ethanol (50 : 50), 然后用生理盐水稀释。
注射用配方 9: EtOH : Corn oil = 10 : 90 (如： 100 μL EtOH → 900 μL Corn oil)
注射用配方 10: EtOH : PEG300：Tween 80 : Saline = 10 : 40 : 5 : 45 (如： 100 μL EtOH → 400 μL PEG300 → 50 μL Tween 80 → 450 μL Saline)

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口服配方 1: 悬浮于0.5% CMC Na (羧甲基纤维素钠)
口服配方 2: 悬浮于0.5% Carboxymethyl cellulose (羧甲基纤维素)
示例: 以口服配方 1 (悬浮于 0.5% CMC Na)为例说明, 如果要配制 100 mL 2.5 mg/mL 的工作液, 您可以先取0.5g CMC Na并将其溶解于100mL ddH2O中，得到0.5%CMC-Na澄清溶液；然后将250 mg待测化合物加到100 mL前述 0.5%CMC Na溶液中，得到悬浮液。

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口服配方 3: 溶解于 PEG400 (聚乙二醇400)
口服配方 4: 悬浮于0.2% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 5: 溶解于0.25% Tween 80 and 0.5% Carboxymethyl cellulose (羧甲基纤维素)
口服配方 6: 做成粉末与食物混合

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注意: 以上为较为常见方法，仅供参考， InvivoChem并未独立验证这些配方的准确性。具体溶剂的选择首先应参照文献已报道溶解方法、配方或剂型，对于某些尚未有文献报道溶解方法的化合物，需通过前期实验来确定（建议先取少量样品进行尝试），包括产品的溶解情况、梯度设置、动物的耐受性等。

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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。