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Identification
- Summary
Arimoclomol is a heat-shock protein co-inducer used to treat neurological symptoms of Niemann-Pick disease type C in combination with miglustat.
- Generic Name
- Arimoclomol
- DrugBank Accession Number
- DB05025
- Background
Arimoclomol is a hydroxylamine derivative 3 and a heat-shock protein-70 (HSP70) co-inducer.7 Arimoclomol was approved by the FDA on September 20, 2024, making it the first treatment for Niemann-Pick disease, type C (NPC).8 It is also being investigated in amyotrophic lateral sclerosis (ALS) 3,6 and inclusion body myositis.4
- Type
- Small Molecule
- Groups
- Approved, Investigational
- Structure
Structure for Arimoclomol (DB05025)
- Weight
- Average: 313.78
Monoisotopic: 313.119319228 - Chemical Formula
- C14H20ClN3O3
- Synonyms
- 3-PYRIDINECARBOXIMIDOYL CHLORIDE, N-((2R)-2-HYDROXY-3-(1-PIPERIDINYL)PROPOXY), 1-OXIDE
- Arimoclomol
- BRX-220 FREE BASE
- N-[(2R)-2-Hydroxy-3-(1-piperidyl)propoxy]pyridine-3-carboximidoyl chloride, 1-oxide
Pharmacology
- Indication
Arimoclomol is indicated for use in combination with miglustat for the treatment of neurological manifestations of Niemann-Pick disease type C (NPC) in adult and pediatric patients two years of age and older.7
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Indication Type Indication Combined Product Details Approval Level Age Group Patient Characteristics Dose Form Used in combination to treat Niemann-pick disease, type c Regimen in combination with: Miglustat (DB00419) •••••••••••• - Contraindications & Blackbox Warnings
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Arimoclomol is a heat shock protein-modulating drug with demonstrated neuroprotective properties in animal models.3 It is used to treat the neurological manifestations of NPC. Arimoclomol reversibly increased mean serum creatinine by 19% from the baseline when it was administered at a dose of 744 mg/day in healthy male adults.7
- Mechanism of action
Lysosomes play a critical role in degrading macromolecules, including cholesterol, within the cell. Niemann-Pick disease, type C (NPC), is an inherited lysosomal storage disease associated with mutations in the NPC1 or NPC2 proteins, which regulate cholesterol content within membranes.2 NPC1 and NPC2 cause cholesterol efflux from late lysosomal and endosomal compartments, and dysfunction of these proteins leads to impaired lysosomal function and the accumulation of multiple lipid species,2 causing perturbed cellular function and cell death.1,2 NPC leads to severe systemic and central nervous system symptoms, such as cognitive impairment, cerebellar ataxia, dysarthria, cataplexy, and seizures.5
The mechanism by which arimoclomol exerts its clinical effects in patients with NPC has not been fully elucidated; however, it is believed to modulate heat shock proteins (HSPs), which are involved in an important cellular defence mechanism against cellular stress such as metabolic or lysosomal stress.2 HSPs, particularly HSP70, are molecular chaperones responsible for the correct processing and folding of damaged or mutated proteins.2,3,6 HSPs increase the activity of sphingolipid‐degrading enzymes, stabilize lysosomal membranes, and exert neuroprotective effects against cell death.2 Arimoclomol is an HSP70 co-inducer that can cross the blood-brain barrier.2 It is proposed to clear protein aggregates.3,1 Arimoclomol is not believed to directly induce HSP or stress cells; instead, it is reported to stabilize the interaction of Heat Shock Factor 1 (HSF1) with Heat Shock Elements (HSEs), which are transcriptional elements that regulate HSP production.1,4
- Absorption
Following the oral administration of 248 mg arimoclomol three times a day in healthy subjects, the geometric mean (CV%) AUC0-8 hours at day one (first dose) and day six (steady-state) were 5317 (17%) hr x ng/mL and 7207 (19%) hr x ng/mL, respectively. The geometric mean (CV%) Cmax at day one (first dose) and day six (steady-state) were 1749 (49%) ng/mL and 2090 (23%) ng/mL, respectively. The median Tmax was approximately 0.5 hours. The absolute bioavailability of arimoclomol following oral administration has not been determined.7
No clinically significant difference in arimoclomol pharmacokinetics was observed following the administration of a high-fat, 1000-calorie, 60% fat meal to healthy subjects.7
- Volume of distribution
The mean apparent volume of distribution (VZ/F) of arimoclomol at steady-state in healthy adult subjects is 211 L. A dose-dependent increase in arimoclomol cerebral spinal fluid concentrations was seen at steady state.7
- Protein binding
The plasma protein binding of arimoclomol is approximately 10%.7
- Metabolism
Arimoclomol is predominantly metabolized through glutathionation, O-glucuronidation and NO-oxime cleavage.7
- Route of elimination
Following a single dose of radiolabeled arimoclomol 100 mg to healthy male subjects under fasted conditions, approximately 12% of the dose was recovered in feces and 77.5% in urine (42% unchanged).7
- Half-life
The elimination half-life of arimoclomol is approximately four hours.7
- Clearance
The mean apparent clearance of arimoclomol (CL/F) at steady state is 34 L/hr in healthy adult subjects.7
- Adverse Effects
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There is no information regarding the acute toxicity (LD50) or overdose of arimoclomol.
- Pathways
- Not Available
- Pharmacogenomic Effects/ADRs
- Not Available
Interactions
- Drug Interactions
- This information should not be interpreted without the help of a healthcare provider. If you believe you are experiencing an interaction, contact a healthcare provider immediately. The absence of an interaction does not necessarily mean no interactions exist.
Drug Interaction Integrate drug-drug
interactions in your softwareAmantadine The serum concentration of Amantadine can be increased when it is combined with Arimoclomol. Choline The serum concentration of Choline can be increased when it is combined with Arimoclomol. Choline salicylate The serum concentration of Choline salicylate can be increased when it is combined with Arimoclomol. Cisplatin The serum concentration of Cisplatin can be increased when it is combined with Arimoclomol. Dalfampridine The serum concentration of Dalfampridine can be increased when it is combined with Arimoclomol. - Food Interactions
- Take with or without food. Food has negligible effects on the pharmacokinetics of arimoclomol.
Products
Drug product information from 10+ global regionsOur datasets provide approved product information including:dosage, form, labeller, route of administration, and marketing period.Access drug product information from over 10 global regions.- Product Ingredients
Ingredient UNII CAS InChI Key Arimoclomol citrate Q85FFY6179 368860-21-3 XSENLDLUMVYRET-BTQNPOSSSA-N Arimoclomol maleate 18D1V854HG 289893-26-1 OHUSJUJCPWMZKR-FEGZNKODSA-N - Brand Name Prescription Products
Name Dosage Strength Route Labeller Marketing Start Marketing End Region Image Miplyffa Capsule 93 mg/1 Oral Acer Therapeutics Inc. 2024-09-20 Not applicable US 
Miplyffa Capsule 62 mg/1 Oral Acer Therapeutics Inc. 2024-09-20 Not applicable US Miplyffa Capsule 124 mg/1 Oral Acer Therapeutics Inc. 2024-09-20 Not applicable US Miplyffa Capsule 47 mg/1 Oral Acer Therapeutics Inc. 2024-09-20 Not applicable US
Categories
- ATC Codes
- N07XX17 — Arimoclomol
- Drug Categories
- Chemical TaxonomyProvided by Classyfire
- Description
- This compound belongs to the class of organic compounds known as pyridinium derivatives. These are compounds containing a pyridinium ring, which is the cationic form of pyridine.
- Kingdom
- Organic compounds
- Super Class
- Organoheterocyclic compounds
- Class
- Pyridines and derivatives
- Sub Class
- Pyridinium derivatives
- Direct Parent
- Pyridinium derivatives
- Alternative Parents
- Piperidines / Heteroaromatic compounds / Trialkylamines / Secondary alcohols / 1,2-aminoalcohols / Azacyclic compounds / Organopnictogen compounds / Organochlorides / Organic oxides / Hydrocarbon derivatives
- Substituents
- 1,2-aminoalcohol / Alcohol / Amine / Aromatic heteromonocyclic compound / Azacycle / Heteroaromatic compound / Hydrocarbon derivative / Organic nitrogen compound / Organic oxide / Organic oxygen compound
- Molecular Framework
- Aromatic heteromonocyclic compounds
- External Descriptors
- Not Available
- Affected organisms
- Not Available
Chemical Identifiers
- UNII
- EUT3557RT5
- CAS number
- 289893-25-0
- InChI Key
- SGEIEGAXKLMUIZ-CYBMUJFWSA-N
- InChI
- InChI=1S/C14H20ClN3O3/c15-14(12-5-4-8-18(20)9-12)16-21-11-13(19)10-17-6-2-1-3-7-17/h4-5,8-9,13,19H,1-3,6-7,10-11H2/t13-/m1/s1
- IUPAC Name
- 3-[chloro({[(2R)-2-hydroxy-3-(piperidin-1-yl)propoxy]imino})methyl]pyridin-1-ium-1-olate
- SMILES
- O[C@@H](CON=C(Cl)C1=C[N+]([O-])=CC=C1)CN1CCCCC1
References
- General References
- Kirkegaard T, Gray J, Priestman DA, Wallom KL, Atkins J, Olsen OD, Klein A, Drndarski S, Petersen NH, Ingemann L, Smith DA, Morris L, Bornaes C, Jorgensen SH, Williams I, Hinsby A, Arenz C, Begley D, Jaattela M, Platt FM: Heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses. Sci Transl Med. 2016 Sep 7;8(355):355ra118. doi: 10.1126/scitranslmed.aad9823. [Article]
- Mengel E, Patterson MC, Da Riol RM, Del Toro M, Deodato F, Gautschi M, Grunewald S, Gronborg S, Harmatz P, Heron B, Maier EM, Roubertie A, Santra S, Tylki-Szymanska A, Day S, Andreasen AK, Geist MA, Havnsoe Torp Petersen N, Ingemann L, Hansen T, Blaettler T, Kirkegaard T, I Dali C: Efficacy and safety of arimoclomol in Niemann-Pick disease type C: Results from a double-blind, randomised, placebo-controlled, multinational phase 2/3 trial of a novel treatment. J Inherit Metab Dis. 2021 Nov;44(6):1463-1480. doi: 10.1002/jimd.12428. Epub 2021 Sep 7. [Article]
- Benatar M, Hansen T, Rom D, Geist MA, Blaettler T, Camu W, Kuzma-Kozakiewicz M, van den Berg LH, Morales RJ, Chio A, Andersen PM, Pradat PF, Lange D, Van Damme P, Mora G, Grudniak M, Elliott M, Petri S, Olney N, Ladha S, Goyal NA, Meyer T, Hanna MG, Quinn C, Genge A, Zinman L, Jabari D, Shoesmith C, Ludolph AC, Neuwirth C, Nations S, Shefner JM, Turner MR, Wuu J, Bennett R, Dang H, Sundgreen C: Safety and efficacy of arimoclomol in patients with early amyotrophic lateral sclerosis (ORARIALS-01): a randomised, double-blind, placebo-controlled, multicentre, phase 3 trial. Lancet Neurol. 2024 Jul;23(7):687-699. doi: 10.1016/S1474-4422(24)00134-0. Epub 2024 May 20. [Article]
- Machado PM, McDermott MP, Blaettler T, Sundgreen C, Amato AA, Ciafaloni E, Freimer M, Gibson SB, Jones SM, Levine TD, Lloyd TE, Mozaffar T, Shaibani AI, Wicklund M, Rosholm A, Carstensen TD, Bonefeld K, Jorgensen AN, Phonekeo K, Heim AJ, Herbelin L, Barohn RJ, Hanna MG, Dimachkie MM: Safety and efficacy of arimoclomol for inclusion body myositis: a multicentre, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2023 Oct;22(10):900-911. doi: 10.1016/S1474-4422(23)00275-2. [Article]
- Vanier MT: Niemann-Pick disease type C. Orphanet J Rare Dis. 2010 Jun 3;5:16. doi: 10.1186/1750-1172-5-16. [Article]
- Benatar M, Wuu J, Andersen PM, Atassi N, David W, Cudkowicz M, Schoenfeld D: Randomized, double-blind, placebo-controlled trial of arimoclomol in rapidly progressive SOD1 ALS. Neurology. 2018 Feb 13;90(7):e565-e574. doi: 10.1212/WNL.0000000000004960. Epub 2018 Jan 24. [Article]
- FDA Approved Drug Products: MIPLYFFA (arimoclomol) capsules, for oral use [Link]
- FDA News Release: FDA Approves First Treatment for Niemann-Pick Disease, Type C [Link]
- External Links
- PubChem Compound
- 208924
- PubChem Substance
- 175426933
- ChemSpider
- 181020
- ChEMBL
- CHEMBL4760607
- ZINC
- ZINC000252516369
- Wikipedia
- Arimoclomol
Clinical Trials
- Clinical Trials
Clinical Trial & Rare Diseases Add-on Data Package
Explore 4,000+ rare diseases, orphan drugs & condition pairs, clinical trial why stopped data, & more. Preview package Phase Status Purpose Conditions Count Start Date Why Stopped 100+ additional columns Unlock 175K+ rows when you subscribe.View sample dataNot Available Available Not Available Niemann-Pick Disease, Type C 1 somestatus stop reason just information to hide 3 Completed Treatment Amyotrophic Lateral Sclerosis (ALS) 1 somestatus stop reason just information to hide 3 Terminated Treatment Amyotrophic Lateral Sclerosis (ALS) 1 somestatus stop reason just information to hide 3 Terminated Treatment Inclusion Body Myositis (IBM) 1 somestatus stop reason just information to hide 2 Completed Treatment Amyotrophic Lateral Sclerosis (ALS) 1 somestatus stop reason just information to hide
Pharmacoeconomics
- Manufacturers
- Not Available
- Packagers
- Not Available
- Dosage Forms
Form Route Strength Capsule Oral 124 mg/1 Capsule Oral 47 mg/1 Capsule Oral 62 mg/1 Capsule Oral 93 mg/1 - Prices
- Not Available
- Patents
- Not Available
Properties
- State
- Solid
- Experimental Properties
- Not Available
- Predicted Properties
Property Value Source Water Solubility 0.237 mg/mL ALOGPS logP 0.45 ALOGPS logP -0.44 Chemaxon logS -3.1 ALOGPS pKa (Strongest Acidic) 14 Chemaxon pKa (Strongest Basic) 9.14 Chemaxon Physiological Charge 1 Chemaxon Hydrogen Acceptor Count 5 Chemaxon Hydrogen Donor Count 1 Chemaxon Polar Surface Area 72 Å2 Chemaxon Rotatable Bond Count 6 Chemaxon Refractivity 82.76 m3·mol-1 Chemaxon Polarizability 32.98 Å3 Chemaxon Number of Rings 2 Chemaxon Bioavailability 1 Chemaxon Rule of Five Yes Chemaxon Ghose Filter No Chemaxon Veber's Rule No Chemaxon MDDR-like Rule No Chemaxon - Predicted ADMET Features
Property Value Probability Human Intestinal Absorption + 0.81 Blood Brain Barrier + 0.8583 Caco-2 permeable - 0.5726 P-glycoprotein substrate Substrate 0.6062 P-glycoprotein inhibitor I Inhibitor 0.699 P-glycoprotein inhibitor II Inhibitor 0.9221 Renal organic cation transporter Inhibitor 0.6469 CYP450 2C9 substrate Non-substrate 0.7069 CYP450 2D6 substrate Non-substrate 0.8045 CYP450 3A4 substrate Non-substrate 0.5082 CYP450 1A2 substrate Non-inhibitor 0.7652 CYP450 2C9 inhibitor Non-inhibitor 0.8513 CYP450 2D6 inhibitor Non-inhibitor 0.753 CYP450 2C19 inhibitor Non-inhibitor 0.6055 CYP450 3A4 inhibitor Non-inhibitor 0.844 CYP450 inhibitory promiscuity Low CYP Inhibitory Promiscuity 0.7542 Ames test Non AMES toxic 0.5 Carcinogenicity Non-carcinogens 0.8385 Biodegradation Not ready biodegradable 0.9964 Rat acute toxicity 2.5777 LD50, mol/kg Not applicable hERG inhibition (predictor I) Weak inhibitor 0.6881 hERG inhibition (predictor II) Inhibitor 0.7547
Spectra
- Mass Spec (NIST)
- Not Available
- Spectra
Spectrum Spectrum Type Splash Key Predicted GC-MS Spectrum - GC-MS Predicted GC-MS splash10-0002-9320000000-160df3497d0f64e71272 Predicted 1H NMR Spectrum 1D NMR Not Applicable Predicted 13C NMR Spectrum 1D NMR Not Applicable - Chromatographic Properties
Collision Cross Sections (CCS)
Adduct CCS Value (Å2) Source type Source [M-H]- 158.81847 predictedDeepCCS 1.0 (2019) [M+H]+ 161.21432 predictedDeepCCS 1.0 (2019) [M+Na]+ 167.97215 predictedDeepCCS 1.0 (2019)
Transporters
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Inhibitor
- General Function
- Electrogenic voltage-dependent transporter that mediates the transport of a variety of organic cations such as endogenous bioactive amines, cationic drugs and xenobiotics (PubMed:9260930, PubMed:9687576). Functions as a Na(+)-independent, bidirectional uniporter (PubMed:21128598, PubMed:9687576). Cation cellular uptake or release is driven by the electrochemical potential, i.e. membrane potential and concentration gradient (PubMed:15212162, PubMed:9260930, PubMed:9687576). However, may also engage electroneutral cation exchange when saturating concentrations of cation substrates are reached (By similarity). Predominantly expressed at the basolateral membrane of hepatocytes and proximal tubules and involved in the uptake and disposition of cationic compounds by hepatic and renal clearance from the blood flow (PubMed:15783073). Implicated in monoamine neurotransmitters uptake such as histamine, dopamine, adrenaline/epinephrine, noradrenaline/norepinephrine, serotonin and tyramine, thereby supporting a physiological role in the central nervous system by regulating interstitial concentrations of neurotransmitters (PubMed:16581093, PubMed:17460754, PubMed:9687576). Also capable of transporting dopaminergic neuromodulators cyclo(his-pro), salsolinol and N-methyl-salsolinol, thereby involved in the maintenance of dopaminergic cell integrity in the central nervous system (PubMed:17460754). Mediates the bidirectional transport of acetylcholine (ACh) at the apical membrane of ciliated cell in airway epithelium, thereby playing a role in luminal release of ACh from bronchial epithelium (PubMed:15817714). Also transports guanidine and endogenous monoamines such as vitamin B1/thiamine, creatinine and N-1-methylnicotinamide (NMN) (PubMed:12089365, PubMed:15212162, PubMed:17072098, PubMed:24961373, PubMed:9260930). Mediates the uptake and efflux of quaternary ammonium compound choline (PubMed:9260930). Mediates the bidirectional transport of polyamine agmatine and the uptake of polyamines putrescine and spermidine (PubMed:12538837, PubMed:21128598). Able to transport non-amine endogenous compounds such as prostaglandin E2 (PGE2) and prostaglandin F2-alpha (PGF2-alpha) (PubMed:11907186). Also involved in the uptake of xenobiotic 4-(4-(dimethylamino)styryl)-N-methylpyridinium (ASP) (PubMed:12395288, PubMed:16394027). May contribute to regulate the transport of organic compounds in testis across the blood-testis-barrier (Probable)
- Specific Function
- acetylcholine transmembrane transporter activity
- Gene Name
- SLC22A2
- Uniprot ID
- O15244
- Uniprot Name
- Solute carrier family 22 member 2
- Molecular Weight
- 62579.99 Da
References
- FDA Approved Drug Products: MIPLYFFA (arimoclomol) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Multidrug efflux pump that functions as a H(+)/organic cation antiporter (PubMed:16330770, PubMed:17509534). Plays a physiological role in the excretion of cationic compounds including endogenous metabolites, drugs, toxins through the kidney and liver, into urine and bile respectively (PubMed:16330770, PubMed:17495125, PubMed:17509534, PubMed:17582384, PubMed:18305230, PubMed:19158817, PubMed:21128598, PubMed:24961373). Mediates the efflux of endogenous compounds such as creatinine, vitamin B1/thiamine, agmatine and estrone-3-sulfate (PubMed:16330770, PubMed:17495125, PubMed:17509534, PubMed:17582384, PubMed:18305230, PubMed:19158817, PubMed:21128598, PubMed:24961373). May also contribute to regulate the transport of cationic compounds in testis across the blood-testis-barrier (Probable)
- Specific Function
- antiporter activity
- Gene Name
- SLC47A1
- Uniprot ID
- Q96FL8
- Uniprot Name
- Multidrug and toxin extrusion protein 1
- Molecular Weight
- 61921.585 Da
References
- FDA Approved Drug Products: MIPLYFFA (arimoclomol) capsules, for oral use [Link]
- Kind
- Protein
- Organism
- Humans
- Pharmacological action
- No
- Actions
- Substrate
- General Function
- Multidrug efflux pump that functions as a H(+)/organic cation antiporter. Mediates the efflux of cationic compounds, such as the model cations, tetraethylammonium (TEA) and 1-methyl-4-phenylpyridinium (MPP+), the platinum-based drug oxaliplatin or weak bases that are positively charged at physiological pH, cimetidine, the platinum-based drugs cisplatin and oxaliplatin or the antidiabetic drug metformin. Mediates the efflux of endogenous compounds such as, creatinine, thiamine and estrone-3-sulfate. Plays a physiological role in the excretion of drugs, toxins and endogenous metabolites through the kidney
- Specific Function
- antiporter activity
- Gene Name
- SLC47A2
- Uniprot ID
- Q86VL8
- Uniprot Name
- Multidrug and toxin extrusion protein 2
- Molecular Weight
- 65083.915 Da
References
- FDA Approved Drug Products: MIPLYFFA (arimoclomol) capsules, for oral use [Link]
Drug created at October 21, 2007 22:23 / Updated at October 10, 2024 16:26