TTR (transthyretin)

Acoramidis 盐酸盐（AG10，0.1-10 μM，TTR ~ 5 μM）比 V122I- 和 WT-TTR 更有效地稳定全血清中的 WT 和突变型 TTR [1]。在 10 至 100 μM 之间，Acoramidis 盐酸盐 (AG10) 以浓度依赖性方式提高线粒体 QO2 [3]。药物开发中两种典型的脱靶，即钾通道 hERG (IC50 > 100 μM) 和几种细胞色素 P450 同工酶 (IC50 > 50 μM)（低毒性），可被 acoramidis 盐酸盐 (AG10) 最小程度地抑制 [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。
孵化时间：72小时。
实验结果：在稳定 TTR 方面比 tafamidis 更有效。 AG10 浓度为 10 µM 可使血清中几乎所有 TTR 稳定。

Animal/Disease Models: Wistar rats[1].
Doses: 50 mg/kg/d (Toxicity Analysis).
Route of Administration: Oral gavage, daily for 28 d.
Experimental Results: demonstrated the plasma Cmax of ∼40 µM and histopathological evaluation of liver, kidney, heart, spleen, thymus, and lung demonstrated no signs of pathologic processes in the AG10-treated animals

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 Hydrochloride is the hydrochloride salt form of acoramidis, 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 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.
ACORAMIDIS HYDROCHLORIDE is a small molecule drug with a maximum clinical trial phase of IV (across all indications) that was first approved in 2024 and is indicated for amyloidosis and male infertility.

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.

C15H18CLFN2O3

328.766426563263

328.098

C, 54.80; H, 5.52; Cl, 10.78; F, 5.78; N, 8.52; O, 14.60

2242751-53-5

Acoramidis;1446711-81-4

135307127

White to light yellow solid powder

75.2

3

5

6

22

356

0

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

MGFZEARHINUOMX-UHFFFAOYSA-N

InChI=1S/C15H17FN2O3.ClH/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);1H

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

Acoramidis hydrochloride; 2242751-53-5; AG10 hydrochloride; AG-10 hydrochloride; VY9C88C2NV;

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)

DMSO: 62.5 mg/mL (190.10 mM)
H2O: < 0.1 mg/mL

配方 1 中的溶解度: ≥ 2.08 mg/mL (6.33 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 20.8 mg/mL澄清DMSO储备液加入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: ≥ 2.08 mg/mL (6.33 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 20.8 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: ≥ 2.08 mg/mL (6.33 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 20.8 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：
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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；
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7、 以上所有助溶剂都可在 Invivochem.cn网站购买。