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 longer-acting, 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.