Dynamic Medicinal Chemistry in the Elaboration of Morphine-6- Glucuronide Analogs

John R. Cashman; James M. MacDougall

Abstract

This review discusses the role of dynamic medicinal chemistry in the design and development of more effective opioids for the treatment of pain. Human Phase II clinical studies have shown that morphine-6-glucuronide (M6G) has equivalent analgesic effects to morphine and an improved side effect profile particularly at reducing the tendency to cause nausea, vomiting, sedation and respiratory depression. Based on these clinical observations, a new class of pain medication could be developed. Despite the promise, M6G is not an ideal drug because bioavailability is low and hydrolysis occurs in the gut. The literature covered includes a comprehensive list of work that illustrates: (i) the role of drug metabolism and drug disposition concepts in M6G analog drug development, (ii) the use of dynamic medicinal chemistry in improving M6G pharmaceutical properties, and (iii) the role of drug metabolism in enhancing bioavailability of M6G. Using optimized dynamic medicinal chemistry procedures for drug design and development, understanding the use of drug development concepts in early drug development and applying new methods from other fields may help advance this field of drug development. This review summarizes studies that support the feasibility of elaborating longeracting, less expensive pain medications with possibly a safer profile of side effects. Development of new pain medications for cancer and other diseases based on M6G could provide novel agents that could balance optimal analgesia with a decreased occurrence of adverse side effects.

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