Acotiamide Hydrochloride

Product Overview

Acotiamide Hydrochloride (development codes YM-443／Z-338) was co-developed by Zeria and Astellas of Japan, approved by Japan’s PMDA on March 25, 2013 under the brand name Acofide. It is the world’s first oral prokinetic agent specifically indicated for functional dyspepsia (FD).

Structural class: a thiazolecarboxamide small molecule — a 1,3-thiazole core bearing at the 2-position, via an amide bond, a 2-hydroxy-4,5-dimethoxybenzoyl group (derived from the asaronic acid scaffold), and at the 4-position a carboxamide linked to an N,N-diisopropylaminoethyl group. The molecule contains one tertiary amine (diisopropylamino) center and is supplied as the hydrochloride salt.

Mechanism of action: an orally active, selective, reversible acetylcholinesterase (AChE) inhibitor. AChE is the enzyme that degrades acetylcholine (ACh); AChE inhibition raises synaptic ACh concentrations, thereby:

• enhancing contractility of the gastric antrum and body;
• improving delayed gastric emptying;
• promoting gastric accommodation (receptive relaxation of the stomach after meals).

Animal and in vitro studies show that at 3 μM it enhances acetylcholine-induced contraction of guinea-pig gastric body and antral muscle strips. Note: its precise mechanism of action has not been fully elucidated; some literature suggests it may also involve modulation of gastric compliance and multiple targets — AChE inhibition is the primary but not the sole mechanism.

Discrepancy in AChE inhibitory potency: different sources report IC50 values of 0.384 μM (Cayman／ChemicalBook citing Ito et al. 2016) and 1.79 μM (certain suppliers and bioactivity descriptions) — the two were measured under different conditions and are not comparable; the source must be cited when quoting.

Clinical positioning: for the improvement of postprandial distress syndrome (PDS) symptoms of functional dyspepsia, including postprandial fullness, upper abdominal bloating, and early satiation.

Technical Specifications

• Standards: CHP／USP／EP

• Specification: 0.99 (purity ≥99.0%, HPLC); reagent grade commonly ≥98%

• CAS No.: 185104-11-4 (acotiamide hydrochloride, anhydrous/non-hydrated hydrochloride; EINECS 203-105-6, UNII 510791NN30, MDL MFCD23103502, DSSTox DTXSID30171717, NCI C72222)

  • Trihydrate (the commonly marketed API form): CAS 773092-05-0, molecular formula C₂₁H₃₀N₄O₅S·HCl·3H₂O, molecular weight 541.06
  • Free base (acotiamide): CAS 185106-16-5, molecular formula C₂₁H₃₀N₄O₅S, molecular weight 450.55
  • All three share the same C₂₁H₃₀N₄O₅S skeleton but differ in molecular weight (487.01／541.06／450.55); the exact form must be specified for formulation and assay conversions

• Molecular formula: C₂₁H₃₀N₄O₅S·HCl (the combined formula may also be written as C₂₁H₃₁ClN₄O₅S)

• Molecular weight: 487.01 (consistent across LookChem, ChemicalBook, and 化工球网; calculated values of 487.013／487.01264 also reported); exact mass 486.1704

• Appearance: white to off-white crystalline powder (the trihydrate is often described as a white to pale yellow/light yellow solid powder); Cayman records it as a crystalline solid

• Purity (HPLC): ≥ 99.0%

• Melting point: No official pharmacopoeial melting point for the anhydrous hydrochloride (185104-11-4) has been found in CHP／USP／EP or other authoritative public sources — the melting point field for this CAS entry on LookChem is N/A. Note on easily confused data: the trihydrate (773092-05-0) has two conflicting reported melting points — 154–156 ℃ (Chinese pharmaceutical technical sources) and 193–195 ℃ (ChemicalBook, CPHI online, etc.), differing by nearly 40 ℃, and these values belong to a different CAS number and must not be entered under the anhydrous hydrochloride entry. If this field is mandatory on the site, it is recommended to state “not applicable” or “as determined by actual measurement”

• Specific optical rotation: not applicable — the molecule contains no chiral center (the two isopropyl groups are enantiotopic-equivalent substituents; no stereocenter)

• Chemical name: N-[2-[bis(1-methylethyl)amino]ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-4-thiazolecarboxamide monohydrochloride; IUPAC: N-[2-(diisopropylamino)ethyl]-2-[(2-hydroxy-4,5-dimethoxybenzoyl)amino]-1,3-thiazole-4-carboxamide hydrochloride

• Stereochemistry: no stereocenters

• Solubility: soluble in DMSO (≥10 mg／mL; some sources report 100 mg/mL); sparingly/slightly soluble in ethanol (0.1–1 mg/mL; also reported as 20 mg/mL), methanol, chloroform (slight, requires heating and sonication); slightly soluble in water (approx. 3–5 mg/mL); the trihydrate dissolves in DMF, is sparingly soluble in methanol, slightly soluble in ethanol and water, very slightly soluble in acetone, and insoluble in ethyl acetate

• Acid dissociation constant (pKa): 7.38 ± 0.50 (calculated, free base)

• Calculated physicochemical parameters: density approx. 1.246 ± 0.06 g/cm³ (predicted, free base); LogP approx. 4.73 (trihydrate reported as 4.534); topological polar surface area approx. 148.24 Ų (trihydrate 175.93); hydrogen bond donors 4／acceptors 8; rotatable bonds 10; heavy atom count 32

• Marketed dosage form: 100 mg tablets (as acotiamide hydrochloride, Acofide in Japan)

• Storage conditions: store sealed, dry, and frozen at −20 ℃; for the trihydrate, 2–8 ℃ is recommended; protect from moisture and light, and storage under an inert gas such as nitrogen is recommended

Applications

• Postprandial distress syndrome of functional dyspepsia (FD) (core indication): for the improvement of postprandial fullness, upper abdominal bloating, and early satiation caused by functional dyspepsia. Approved by Japan’s PMDA on March 25, 2013 — the world’s first oral prokinetic agent targeting FD

• Gastroprokinetic activity (pharmacological action): enhances antral and gastric body motility, improves delayed gastric emptying, and promotes gastric accommodation; enhanced postprandial antral motility has been demonstrated in both rat and dog models

• Pharmacology and mechanism research: used for evaluation of acetylcholinesterase inhibitory activity (IC50 determination), AChE selectivity (versus butyrylcholinesterase) and reversibility studies, in vitro gastrointestinal smooth muscle contraction assays (guinea-pig gastric body/antral strips), animal models of gastric emptying and gastric compliance, and research on functional dyspepsia-related gastrointestinal motility disorders and intestinal inflammation

• Formulation and manufacturing: used in formulation development of tablets (100 mg); the API has limited water solubility, so formulations must balance dissolution and stability; key manufacturing control points include related substances (particularly amide bond hydrolysis products, thiazole ring-related impurities, and diisopropylaminoethyl side-chain impurities), assay, water content (the trihydrate requires control of water of crystallization), and residual solvents; suitable for analytical method development and validation, stability studies, impurity reference standards, and GMP scale-up and CMO／CDMO contract manufacturing

Safety notice: This product is an active pharmaceutical ingredient (API) intended only for legitimate industrial, research, and pharmaceutical manufacturing use; it is not for end-user clinical use or self-medication guidance. The finished product is a prescription drug and should be used under the guidance of a physician; organic diseases causing similar symptoms (such as peptic ulcer, gastroesophageal reflux disease, malignancy, etc.) should be excluded before treatment. Contraindications: patients with a history of hypersensitivity to any component of this product. Use with caution: pregnant and lactating women (safety not established), children (no clinical experience), the elderly (reduced physiological function; close observation required), and patients with hepatic or renal impairment. Adverse reactions: nausea, vomiting, diarrhea, constipation, abdominal pain, headache, dizziness, rash, and pruritus have been observed in clinical trials, as well as abnormal laboratory values (e.g., elevated ALT／AST, elevated blood urea nitrogen). Drug interactions: because this product inhibits AChE, concomitant use with anticholinergic drugs may mutually weaken their effects; concomitant use with cholinergic agonists may enhance effects — combination use should be undertaken with caution and close observation. When handling the API, protective gloves, protective clothing, and eye/face protection are recommended; avoid dust inhalation.

Product information: please contact us. This information is for reference only.