Opioids are widely used for pain management in moderate-to-severe pain, but some addverse effects such as constipation and emesis/vomitting frequently appear. Opioid receptor antagonists are reported to be effective on these opioid-induced adverse effects. To reduce these undesired effects, we performed synthesis and structure-activity relationship of morphinane derivatives, and obtained promising novel chemotype and lead compound with strong inhibitory effects on opioid receptors. Further improvement of potencies and PK profiles of the lead compound finally led to discover Naldemedine (S-297995), which demonstrated outstandingly strong anti-constipation effect on small intestinal transit model in rat and anti-emetic effect on ferret model.

Discovery of naldemedine (S-297995): A potent and orally available opioid receptor antagonist for treatment of opioid-induced adverse effects

254th National Meeting (2017)

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