Minodronic Acid

Mechanism of action

Third-generation bisphosphonates, including minodronic acid hydrate, contain an amino group in the imidazole ring and are even more powerful inhibitors of bone resorption. With regard to inhibition of bone resorption, minodronic acid hydrate is 1000 times more effective than etidronate and 10–100 times more effective than alendronic acid. Following administration, minodronic acid hydrate specifically accumulates in the bone. It is then separated from the bone by acid released by osteoclasts during the bone resorption process and selectively taken up by osteoclasts. Conventional bisphosphonates were believed to inhibit bone resorption through the induction of osteoclast apoptosis after being taken up by these cells[1].

Clinical Use

The bone resorption inhibitor minodronic acid hydrate was approved and introduced last year in Japan, bringing the total number of bis-phosphonates marketed for this indication to seven. There are an estimated 10 million current and potential osteoporosis sufferers in Japan, a number that is expected to continue growing due to the country’s aging population. Minodronic acid is the first drug to show a significant effect in preventing bone fractures as compared to placebo in a Japanese patient population. Minodronic acid was co-developed by Astellas and Ono, who are marketing the drug as Bonoteo and Recalbon, respectively.

Synthesis

Several syntheses of minodronic acid have been reported,a scalable preparation is described in the scheme. Commercially available acid chloride 71 was first reduced with lithium tritertbutoxy aluminum hydride to the aldehyde 72 at 80??C in 61% yield. Next, reaction of aldehyde 72 with TMSCl and triethylamine generated the corresponding silyl enol ether, which was then treated with bromine to give a-bromoaldehyde 73 in 62% yield. Condensation with 2-amino pyridine furnished imidazopyridine 74, which was hydrolyzed with HCl to acid 75 in 58% yield. Reaction with H3PO3 at 120??C to provide minodronic acid hydrate (XII) in 53% yield.

References

[1] Shinji Tanishima, Yasuo Morio. “A review of minodronic acid hydrate for the treatment of osteoporosis.” Clinical Interventions in Aging 8 (2013): 185–9.