Tuesday, January 19, 2016

Acotiamide | Acetylcholinesterase Inhibitor | Muscarinic Receptor Inhibitior | Treatment for Functional Dyspepsia

Acotiamide [N-{2-[Bis(1-methylethyl)amino]ethyl}-2-{[(2-hydroxy-4,5-dimethoxyphenyl)carbonyl]amino}-1,3-thiazole-4-carboxamide] is an oral first-in-class prokinetic drug for the treatment of patients with functional dyspepsia. In 2013, Acotiamide became the world’s first approved treatment for functional dyspepsia diagnosed by Rome III criteria, with its first approval occurring in Japan [1].

Acotiamide: 3D Structure predicts an Intramolecular Hydrogen Bond

The drug was approved in Japan in March 2013 with a registered name of Acofide and launched in Japan in June 2013. The recommended dosage of acotiamide is 100 mg taken three times daily prior to a meal.
The drug modulates upper gastrointestinal motility to alleviate abdominal symptoms resulting from hypomotility and delayed gastric emptying. It exerts its activity in the stomach via muscarinic receptor inhibition, resulting in enhanced acetylcholine release and inhibition of acetylcholinesterase activity.
Unlike other prokinetic drugs like Cisapride that are utilized in the management of functional dyspepsia, acotiamide shows little/no affinity for serotonin or dopamine D2 receptors.
Acotiamide is discovered by Zeria Pharmaceutical Co. Ltd and co-developed by Astellas Pharma Inc.

Acotiamide Synthesis

US6197970B1: Quoted as industrial process.


1H NMR (Estimated) for Acotiamide

Experimental: 1H-NMR(DMSO-d6) δ: 1.32(6H, d), 1.35(6H, d), 3.17(2H, brs), 3.55-3.70(4H, m), 3.77(3H, s), 3.82(3H, s), 6.87(1H, s), 7.49(1H, s), 7.89(1H, s), 8.23(1H, t), 9.65(1H, brs), 11.79(1H, s), 12.07(1H, brs)


The most commonly reported averse events (AEs) were headache, diarrhea and a rise in prolactin level. Less than 5% of patients also reported cases with increased triglyceride levels, nasopharyngitis, and increased serum γ-glutamyltransferase levels.

One important consideration comes from the fact that inhibition of acetylcholinesterase and inhibition of muscarinic M1 and M2 receptors has a potential to affect a number of systems, including the respiratory and urinary tract. No AEs related to potential anti-cholinergic effects in these systems have been reported.

1. Nolan, M. L.; et. al. Acotiamide: First Global Approval. Drugs 2013, 73(12), 1377-1383.
2. Nagasawa, M.; et. al. Process for producing 2-hydroxybenzamide derivatives. US6197970B1