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On November 22, 2024, The U.S. Food and Drug Administration has approved Attruby (acoramidis) to treat adults with cardiomyopathy (disorder that affects heart muscle) of wild-type or variant (hereditary) transthyretin-mediated amyloidosis (ATTR-CM) to reduce death and hospitalization related to heart problems. Attruby is taken orally, twice daily.
Physicochemical Properties
| Molecular Formula | C15H18CLFN2O3 |
| Molecular Weight | 328.766426563263 |
| Exact Mass | 328.098 |
| Elemental Analysis | C, 54.80; H, 5.52; Cl, 10.78; F, 5.78; N, 8.52; O, 14.60 |
| CAS # | 2242751-53-5 |
| Related CAS # | Acoramidis;1446711-81-4 |
| PubChem CID | 135307127 |
| Appearance | White to light yellow solid powder |
| Hydrogen Bond Donor Count | 3 |
| Hydrogen Bond Acceptor Count | 5 |
| Rotatable Bond Count | 6 |
| Heavy Atom Count | 22 |
| Complexity | 356 |
| Defined Atom Stereocenter Count | 0 |
| SMILES | Cl.FC1=CC=C(C(=O)O)C=C1OCCCC1C(C)=NNC=1C |
| InChi Key | MGFZEARHINUOMX-UHFFFAOYSA-N |
| InChi Code | 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 |
| Chemical Name | 3-[3-(3,5-dimethyl-1H-pyrazol-4-yl)propoxy]-4-fluorobenzoic acid;hydrochloride |
| Synonyms | Acoramidis hydrochloride; 2242751-53-5; AG10 hydrochloride; AG-10 hydrochloride; VY9C88C2NV; |
| HS Tariff Code | 2934.99.9001 |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: Please store this product in a sealed and protected environment, avoid exposure to moisture. |
| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | TTR (transthyretin) |
| ln Vitro | Acoramidis hydrochloride (AG10, 0.1-10 μM, TTR ~ 5 μM) stabilized WT and mutant TTR in whole serum more effectively than it did V122I- and WT-TTR [1]. Between 10 and 100 μM, Acoramidis hydrochloride (AG10) raises mitochondrial QO2 in a concentration-dependent manner [3]. Two typical off-targets in drug development, the potassium channel hERG (IC50 > 100 μM) and several cytochrome P450 isozymes (IC50 > 50 μM) (low toxicity), are minimally inhibited by acoramidis hydrochloride (AG10) [1]. |
| ln Vivo |
Mechanism of Action
The first and rate-limiting step in transthyretin (TTR) amyloidogenesis is the dissociation of the TTR tetramer into its constituent monomers. This is followed by misfolding of the resulting monomer and their subsequent aggregation, leading to build-ups of larger oligomers and amyloid fibrils. When these build-ups aggregate in the heart, they can lead to heart dysfunction (transthyretin amyloidosis cardiomyopathy; ATTR-CM). Acoramidis is a highly selective stabilizer of TTR. It exerts its therapeutic effects by binding to TTR at thyroxine binding sites and stabilizing it in its tetrameric form, thereby slowing the rate-limiting step in amyloidogenesis. Pharmacodynamics At the recommended dosage, near-complete _in vitro_ transthyretin (TTR) stabilization was observed as early as Day 28 and through completion of a 30-month study of patients with ATTR-CM (wild-type and variant). Acoramidis may decrease serum concentrations of free thyroxine without an accompanying change in thyroid stimulating hormone - this is an effect common to TTR stabilizers, and is likely due to reduced thyroxine binding to (or displacement from) TTR. Acoramidis is a small molecule stabilizer of transthyretin (TTR) for use in patients with TTR amyloidosis. Similar to the previously developed [tafamidis], acoramidis is used to stabilize TTR in its tetrameric form, preventing the formation of amyloidogenic monomers and the progression of amyloidosis. Although they share a mechanism of action, acoramidis is more selective for TTR and is a more potent stabilizer when compared to tafamidis. Acoramidis has been in development since at least 2013. It was brought to market by BridgeBio Pharma and approved by the FDA in November 2024 to reduce negative cardiovascular outcomes in patients with cardiomyopathy caused by TTR amyloidosis. Acoramidis is a Transthyretin Stabilizer. The mechanism of action of acoramidis is as a Transthyretin Stabilizer, and Cytochrome P450 2C9 Inhibitor. Acoramidis is transthyretin stabilizer used for the treatment of adults with the cardiomyopathy of both wild-type and hereditary transthyretin-mediated amyloidosis to reduce cardiovascular morbidity and mortality. Acoramidis has been associated with minor liver test abnormalities during therapy but has not been linked instances of clinically apparent liver injury. 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 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 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 and has 3 investigational indications. |
| Cell Assay |
Western Blot Analysis[1]. Cell Types: Human serum (TTR ∼5 µM). Tested Concentrations: 0.1 and 10 μM. Incubation Duration: 72 h. Experimental Results: Was Dramatically more effective than tafamidis in stabilizing TTR. The concentration of AG10 to 10 µM resulted in stabilization of almost all of TTR in serum. |
| Animal Protocol |
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 |
| ADME/Pharmacokinetics |
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. |
| Toxicity/Toxicokinetics |
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. |
| References |
[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. |
| Additional Infomation |
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. Drug Indication Treatment of transthyretin amyloidosis (ATTR) 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. |
Solubility Data
| Solubility (In Vitro) |
DMSO: 62.5 mg/mL (190.10 mM) H2O: < 0.1 mg/mL |
| Solubility (In Vivo) |
Solubility in Formulation 1: ≥ 2.08 mg/mL (6.33 mM) (saturation unknown) in 10% DMSO + 40% PEG300 + 5% Tween80 + 45% Saline (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 400 μL PEG300 and mix evenly; then add 50 μL Tween-80 to the above solution and mix evenly; then add 450 μL normal saline to adjust the volume to 1 mL. Preparation of saline: Dissolve 0.9 g of sodium chloride in 100 mL ddH₂ O to obtain a clear solution. Solubility in Formulation 2: ≥ 2.08 mg/mL (6.33 mM) (saturation unknown) in 10% DMSO + 90% (20% SBE-β-CD in Saline) (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of 20% SBE-β-CD physiological saline solution and mix evenly. Preparation of 20% SBE-β-CD in Saline (4°C，1 week): Dissolve 2 g SBE-β-CD in 10 mL saline to obtain a clear solution. Solubility in Formulation 3: ≥ 2.08 mg/mL (6.33 mM) (saturation unknown) in 10% DMSO + 90% Corn Oil (add these co-solvents sequentially from left to right, and one by one), clear solution. For example, if 1 mL of working solution is to be prepared, you can add 100 μL of 20.8 mg/mL clear DMSO stock solution to 900 μL of corn oil and mix evenly. (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 3.0416 mL | 15.2082 mL | 30.4164 mL | |
| 5 mM | 0.6083 mL | 3.0416 mL | 6.0833 mL | |
| 10 mM | 0.3042 mL | 1.5208 mL | 3.0416 mL |