Bevenopran
[CAS# 676500-67-7]

Identification

• Classification: Biochemical >> Inhibitor >> Neuronal signaling >> Opioid receptor antagonist
• Name: Bevenopran
• Synonyms: 5-[2-methoxy-4-[[2-(oxan-4-yl)ethylamino]methyl]phenoxy]pyrazine-2-carboxamide
• Molecular Formula: C₂₀H₂₆N₄O₄
• Molecular Weight: 386.44
• CAS Registry Number: 676500-67-7
• SMILES: COC1=C(C=CC(=C1)CNCCC2CCOCC2)OC3=NC=C(N=C3)C(=O)N

Discovory and Applicatios

Bevenopran is a synthetic small-molecule drug developed as a peripherally acting μ-opioid receptor antagonist (PAMORA). Its primary mechanism of action is the selective inhibition of μ-opioid receptors located in the gastrointestinal (GI) tract, without significant penetration into the central nervous system (CNS). This pharmacological profile was designed to counteract opioid-induced constipation (OIC), a common and often treatment-limiting side effect of chronic opioid therapy for pain management.

Bevenopran, also known by its developmental code AX-767 and previously as CB-5945, was investigated for its ability to restore normal GI motility in patients receiving opioid analgesics. In healthy individuals and patients, opioids reduce intestinal peristalsis through activation of peripheral μ-opioid receptors, leading to delayed transit time and constipation. Bevenopran blocks this action locally in the gut while preserving the centrally mediated analgesic effects of opioids by minimizing its entry across the blood-brain barrier.

Chemically, bevenopran is a tertiary amine with a polar structure, incorporating multiple functional groups designed to limit CNS penetration. Its oral bioavailability and pharmacokinetic characteristics were optimized for convenient once-daily dosing. Preclinical and early clinical studies demonstrated its antagonistic activity at μ-opioid receptors, as well as limited systemic adverse effects typically associated with CNS-active opioid antagonists such as naloxone or naltrexone.

Bevenopran entered clinical trials and was evaluated in phase 2 studies for its efficacy in treating OIC in patients with chronic non-cancer pain. The studies reported that bevenopran significantly improved bowel function in patients without compromising analgesia. However, despite promising early data, further development was ultimately discontinued. The decision to halt development was based on strategic or commercial considerations rather than definitive failure in clinical outcomes or safety concerns.

The emergence of other PAMORAs, such as methylnaltrexone, naloxegol, and naldemedine, which successfully reached the market, may have influenced the competitive landscape. These agents share a similar therapeutic target and mechanism, and are now approved for use in treating opioid-induced constipation under specific indications.

Although bevenopran is not currently marketed, its development contributed to the broader understanding of peripheral μ-opioid antagonism and drug design strategies that separate central and peripheral opioid effects. Its pharmacological design, targeting peripherally located opioid receptors without CNS interference, remains a guiding principle for future drugs intended to manage opioid side effects.

In summary, bevenopran is a peripherally selective μ-opioid receptor antagonist that was developed to alleviate opioid-induced constipation without affecting central analgesia. Although it did not advance to commercial use, it played a role in the research and development of the PAMORA class of therapeutics aimed at improving the quality of life for patients receiving long-term opioid therapy.

References

2014. Narcotic Bowel Syndrome and Opioid-Induced Constipation. Current Gastroenterology Reports, 16(10).
DOI: 10.1007/s11894-014-0410-4

2013. Opioid-Induced Bowel Dysfunction. Current Gastroenterology Reports, 15(10).
DOI: 10.1007/s11894-013-0344-2

2013. Patients receiving opioids for pain usually require additional pharmacological treatment for opioid-induced constipation. Drugs & Therapy Perspectives, 29(3).
DOI: 10.1007/s40267-013-0019-y