Azelaprag
[CAS# 2049980-18-7]

Identification

• Classification: Biochemical >> Inhibitor >> G protein coupled receptor(GPCR & G Protein)
• Name: Azelaprag
• Synonyms: (2S,3R)-N-[4-(2,6-dimethoxyphenyl)-5-(5-methylpyridin-3-yl)-1,2,4-triazol-3-yl]-3-(5-methylpyrimidin-2-yl)butane-2-sulfonamide
• Molecular Formula: C₂₅H₂₉N₇O₄S
• Molecular Weight: 523.61
• CAS Registry Number: 2049980-18-7
• SMILES: CC1=CC(=CN=C1)C2=NN=C(N2C3=C(C=CC=C3OC)OC)NS(=O)(=O)[C@@H](C)[C@H](C)C4=NC=C(C=N4)C

Properties

• Density: 1.4±0.1 g/cm³ Calc.^*
• Boiling point: 738.0±70.0 ºC 760 mmHg (Calc.)^*
• Flash point: 400.2±35.7 ºC (Calc.)^*
• Index of refraction: 1.65 (Calc.)^*
• Solubility: DMSO 60 mg/mL

^* Calculated using Advanced Chemistry Development (ACD/Labs) Software.

Safety Data

• Hazard Symbols: GHS07 Warning
• Hazard Statements: H302-H315-H319
• Precautionary Statements: P501-P270-P264-P280-P302+P352-P337+P313-P305+P351+P338-P362+P364-P332+P313-P301+P312+P330

Discovory and Applicatios

Azelaprag is a synthetic small-molecule compound that has been studied primarily for its pharmacological activity as a motilin receptor agonist. Motilin is a peptide hormone secreted by endocrine cells in the small intestine, playing a key role in regulating gastrointestinal motility, especially during fasting periods. Azelaprag, also known by its research code names including TAK-954, has been developed to mimic the activity of motilin, thereby stimulating gastrointestinal contractions through activation of the motilin receptor.

The discovery of azelaprag was driven by the need for effective agents to manage disorders associated with delayed gastric emptying, particularly gastroparesis and related gastrointestinal motility disorders. Gastroparesis is a chronic condition in which the stomach takes too long to empty its contents, causing symptoms such as nausea, bloating, and early satiety. Traditional therapies for gastroparesis include prokinetic agents like metoclopramide and erythromycin. However, these treatments are associated with limitations such as tolerance, side effects, and inconsistent efficacy. This unmet medical need led to interest in targeting the motilin receptor pathway with more selective and potent agents.

Azelaprag was designed to act as a selective agonist of the motilin receptor, a G protein-coupled receptor expressed primarily in the gastrointestinal tract. Unlike erythromycin, which was one of the earliest known motilin receptor agonists but is also a macrolide antibiotic, azelaprag is not an antibiotic and does not carry the same risk of antimicrobial resistance or related adverse effects. Its chemical structure allows for high receptor affinity and specificity, with the goal of providing prokinetic activity without off-target pharmacological actions.

Preclinical studies demonstrated that azelaprag could enhance gastric motility and induce phase III migrating motor complexes, a hallmark of motilin activity in the upper gastrointestinal tract. These findings suggested its potential as a treatment for conditions involving impaired gastric emptying. Based on this preclinical efficacy, azelaprag advanced into clinical trials to evaluate its pharmacokinetics, tolerability, and prokinetic effects in human subjects.

Clinical investigations focused on its application in patients with postoperative ileus and gastroparesis. Postoperative ileus is a temporary impairment of bowel motility following surgery, often resulting in discomfort, nausea, and delayed recovery. Azelaprag was evaluated for its ability to shorten the duration of ileus by stimulating coordinated gastrointestinal contractions. In early clinical trials, the compound was reported to be generally well tolerated, and its prokinetic activity supported further exploration in gastrointestinal motility disorders.

Azelaprag represents a class of motilin receptor agonists that have been developed with improved pharmacodynamic and pharmacokinetic profiles compared to older agents. Its selectivity for the motilin receptor and non-antibiotic nature are key features that distinguish it from erythromycin and other macrolides. Additionally, oral bioavailability and systemic exposure of azelaprag have been characterized to support its suitability for clinical use, though ongoing research is necessary to confirm long-term safety and efficacy in broader patient populations.

While azelaprag has not yet been approved as a therapeutic drug in any major market, its development reflects continued interest in gastrointestinal motility pharmacotherapy. The selective targeting of gut peptide hormone receptors like the motilin receptor is part of a broader strategy to manage complex digestive disorders using mechanism-based, receptor-specific interventions. As research continues into the motilin signaling pathway and its role in gut physiology, compounds like azelaprag may play an important role in future treatment paradigms for patients with impaired gastric motility.

References

2020. Cardiovascular response to small-molecule APJ activation. JCI Insight, 5(8).
DOI: 10.1172/jci.insight.132898

2021. Identification of 6-Hydroxypyrimidin-4(1H)-one-3-carboxamides as Potent and Orally Active APJ Receptor Agonists. ACS Medicinal Chemistry Letters, 12(11).
DOI: 10.1021/acsmedchemlett.1c00385

2024. After obesity drugs� success, companies rush to preserve skeletal muscle. Nature Biotechnology, 42(3).
DOI: 10.1038/s41587-024-02176-5