TTR (transthyretin)

与稳定 V122I- 和 WT-TTR 的方式类似，Acoramidis（AG10，0.1-10 μM，TTR ∼5 μM）同样比稳定全血清中的 WT 和突变 TTR 更有效 [1]。在 10 至 100 μM 之间，Acoramidis (AG10) 以浓度依赖性方式提高线粒体 QO2 [3]。 Acoramidis (AG10) 对药物发现中两种常见的脱靶几乎没有抑制作用：几种细胞色素 P450 同工酶 (IC50 > 50 µM)（低毒性）和钾通道 hERG (IC50 > 100 µM) [1]。

作用机制: 转甲状腺素蛋白淀粉样变性的首个且限速步骤是TTR四聚体解离为其组成的单体。随后，生成的单体发生错误折叠并聚集，形成更大的寡聚体和淀粉样原纤维。当这些聚集体在心脏中沉积时，可导致心脏功能障碍（转甲状腺素蛋白淀粉样变性心肌病，ATTR-CM）。阿可拉米司是一种高度选择性的TTR稳定剂，通过与TTR的甲状腺素结合位点结合，将其稳定在四聚体形式，从而减缓淀粉样变性的限速步骤，发挥治疗作用。

药效学: 在推荐剂量下，针对野生型及遗传性ATTR-CM患者为期30个月的研究显示，早在第28天即可观察到近乎完全的体外TTR稳定效果，并持续至研究结束。阿可拉米司可能降低血清游离甲状腺素浓度，但不伴随促甲状腺激素水平变化——此为TTR稳定剂的常见效应，可能因甲状腺素与TTR的结合减少（或被置换）所致。
阿可拉米司是一种用于治疗TTR淀粉样变性的小分子TTR稳定剂。与先前开发的[他法米司]类似，阿可拉米司通过稳定TTR四聚体结构，阻止淀粉样变性单体的形成及疾病进展。尽管作用机制相同，但相较于他法米司，阿可拉米司对TTR的选择性更高，稳定作用更强。该药物至少自2013年开始研发，由BridgeBio Pharma公司推向市场，并于2024年11月获FDA批准，用于降低TTR淀粉样变性所致心肌病患者的不良心血管结局风险。
阿可拉米司属于转甲状腺素蛋白稳定剂，其作用机制包括稳定转甲状腺素蛋白及抑制细胞色素P450 2C9。
该药物用于治疗成人的野生型及遗传性转甲状腺素蛋白介导的淀粉样变性心肌病，以降低心血管疾病发病率和死亡率。治疗期间可能出现轻微的肝功能检测异常，但尚未发现与 clinically apparent肝损伤相关。
阿可拉米司是一种强效、高选择性、口服生物可利用的TTR稳定剂，具有潜在的疾病修正活性。口服给药后，通过与TTR结合并稳定其结构，阻止四聚体解离为单体，从而预防TTR蛋白错误折叠，抑制淀粉样原纤维形成及其在心脏和周围神经中的沉积。TTR是一种由肝脏分泌至血液中的甲状腺素和视黄醇转运蛋白，其淀粉样原纤维的积累可导致心室壁增厚和僵硬，进而引发心力衰竭。
阿可拉米司是一种小分子药物，最高临床试验阶段为IV期（针对所有适应症），于2024年首次获批，目前获批适应症包括淀粉样变性和男性不育症，另有3项适应症处于研究阶段。

蛋白质印迹分析[1]。
细胞类型：人血清（TTR ∼5 µM）。
测试浓度：0.1 和 10 μM。
孵化持续时间：72小时。
实验结果：在稳定TTR方面比Famidy更有效。浓度为 10 µM 的 AG10 可以稳定血清中几乎所有的 TTR。

Animal/Disease Models: Wistar rat[1].
Doses: 50 mg/kg/d (toxicity analysis).
Route of Administration: Orally administered one time/day for 28 days.
Experimental Results: Plasma Cmax of AG10-treated animals was shown to be approximately 40 µM, and histopathological evaluation of liver, kidney, heart, spleen, thymus, and lungs demonstrated no evidence of pathological processes.

Absorption
At steady-state - achieved by day 4 with at a dose of 712 mg twice daily - the mean Cmax and AUC0-12H of acoramidis were 13700 ng/mL and 47200 ng.h/mL, respectively. The Tmax is approximately 1 hour following oral administration.

Route of Elimination
Following the administration of a single 712 mg oral dose of radiolabeled acoramidis, approximately 32% of the radioactivity was recovered in the feces (15% as unchanged parent drug) and approximately 68% was recovered in the urine (<10% as unchanged parent drug).

Volume of Distribution
At steady-state, the apparent volume of distribution for acoramidis is 654 liters.

Clearance
At steady-state, the apparent clearance of acoramidis is 16 L/h.

Protein Binding
_In vitro_, acoramidis is 96% protein-bound, primarily to TTR.

Metabolism / Metabolites
Acoramidis is primarily metabolized by glucuronidation via UGT1A9, UGT1A1, and UGT2B7. The predominant circulating metabolite is acoramidis-β-D-glucuronide (acoramidis acylglucuronide; acoramidis-AG), comprising 8% of total circulating drug-related moieties. The pharmacological activity of acoramidis-AG is approximately 1/3 that of acoramidis parent drug and thus does not significantly contribute to overall pharmacological activity.

Biological Half-Life
The effective half-life of acoramidis is approximately 6 hours.

Hepatotoxicity
In the registration trial of acoramidis, transient mild ALT and AST elevations were not uncommon, but elevations in ALT above 3 times ULN were infrequent and no more common with acoramidis than placebo (0.9% vs 0.5%), most of which were attributed to heart failure or its treatment. No patient required drug discontinuation because of liver test abnormalities and none developed clinically apparent liver injury or elevations in serum aminotransferases accompanied by jaundice. Since its approval, clinical experience with acoramidis has been limited, but there have been no published case reports of clinically apparent liver injury attributed to its use.
Likelihood score: E (unlikely cause of clinically apparent liver injury).

Effects During Pregnancy and Lactation
◉ Summary of Use during Lactation
No information is available on the use of acoramidis during breastfeeding. If a mother requires acoramidis, it is not a reason to discontinue breastfeeding. Until more data become available, acoramidis should be used with caution during breastfeeding, especially while nursing a newborn or preterm infant. Monitor the breastfed infant for gastrointestinal adverse reactions, such as diarrhea.
◉ 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.

[1]. AG10 inhibits amyloidogenesis and cellular toxicity of the familial amyloid cardiomyopathy-associated V122I transthyretin. Proc Natl Acad Sci U S A. 2013 Jun 11;110(24):9992-7.

[2]. First-in-Human Study of AG10, a Novel, Oral, Specific, Selective, and Potent Transthyretin Stabilizer for the Treatment of Transthyretin Amyloidosis: A Phase 1 Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Study in Healthy Adult Volunteers. Clin Pharmacol Drug Dev. 2020 Jan;9(1):115-129.

[3]. Evidence that tyrphostins AG10 and AG18 are mitochondrial uncouplers that alter phosphorylation-dependent cell signaling. J Biol Chem. 2004 Mar 19;279(12):10910-8.

Acoramidis is a potent, highly selective, orally bioavailable transthyretin (TTR) stabilizer with potential disease-modifying activity. Upon oral administration, acoramidis binds to and stabilizes transthyretin (TTR), thereby preventing tetramer dissociation into monomers. This prevents misfolding of the TTR protein and inhibits the formation of TTR amyloid fibrils and the subsequent deposition of these insoluble protein clusters in the heart and peripheral nerves. TTR is a 127 amino acid transport protein for thyroxine and retinol and is secreted by the liver into the blood. The accumulation of TTR amyloid fibrils may result in thickening and stiffening of the ventricular wall, leading to heart failure.

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Drug Indication
Treatment of transthyretin amyloidosis (ATTR)

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Disease or Condition
ATTR-CM is a rare and serious disease that affects the heart muscle. In patients with ATTR-CM, there is a build-up of protein deposits in the heart, causing the walls of the heart to become stiff, and making the left ventricle unable to properly relax and fill with blood (called cardiomyopathy). As the condition progresses, the heart can become unable to pump blood out adequately, causing heart failure.
There are two types of ATTR-CM, hereditary ATTR-CM (hATTR-CM) and wild-type ATTR-CM (wATTR-CM). In hATTR-CM, which can run in families, there’s a variant in the transthyretin gene, which results in protein deposits in the heart. In wATTR-CM, there is no variant in the transthyretin gene.
While the true prevalence of ATTR-CM is unknown, increasing awareness and enhanced diagnostic tools have led to increasing estimates of the number of patients with ATTR-CM.

Effectiveness
The efficacy and safety of Attruby were evaluated in a multicenter, international, randomized, double-blind, placebo-controlled study in 611 adult patients with wild-type or hereditary (variant) ATTR-CM (NCT03860935).
The primary endpoint of the study included all-cause mortality and cumulative frequency of cardiovascular-related hospitalizations (CVH) over 30 months. At 30 months, more patients taking Attruby vs placebo were alive (81% vs 74%) and there were fewer CVH in those taking Attruby vs placebo (mean number of 0.3 vs 0.6 per year).

Safety Information
The most common adverse reactions were diarrhea and upper abdominal pain. Most of these gastrointestinal adverse reactions were categorized as mild and resolved without drug discontinuation.

Designations
Attruby received orphan drug designation for this indication.

C15H17FN2O3

292.305487394333

292.122

C, 61.63; H, 5.86; F, 6.50; N, 9.58; O, 16.42

1446711-81-4

Acoramidis hydrochloride;2242751-53-5

71464713

White to off-white solid powder

1.3±0.1 g/cm3

542.5±50.0 °C at 760 mmHg

281.9±30.1 °C

0.0±1.5 mmHg at 25°C

1.579

3.73

75.2

2

5

6

21

356

0

FC1=CC=C(C(=O)O)C=C1OCCCC1C(C)=NNC=1C

WBFUHHBPNXWNCC-UHFFFAOYSA-N

InChI=1S/C15H17FN2O3/c1-9-12(10(2)18-17-9)4-3-7-21-14-8-11(15(19)20)5-6-13(14)16/h5-6,8H,3-4,7H2,1-2H3,(H,17,18)(H,19,20)

3-[3-(3,5-dimethyl-1H-pyrazol-4-yl)propoxy]-4-fluorobenzoic acid

Acoramidis; 1446711-81-4; AG-10; AG10; 3-[3-(3,5-Dimethyl-1h-Pyrazol-4-Yl)propoxy]-4-Fluorobenzoic Acid;

2934.99.9001

Powder      -20°C    3 years

                     4°C     2 years

In solvent   -80°C    6 months

                  -20°C    1 month

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

DMSO: ~100 mg/mL (342 mM)

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。