Diquafosol (INS-365) was approved in Japan in 2010 as a 3%
ophthalmic solution for treatment of dry eye disease. Clinical diagnosis of dry eye is difficult because the condition
presents a variety of symptoms. Treatment options include tear
supplements (lubricants), anti-inflammatory drugs (e.g., cyclosporine
eye drops or steroid eye drops), and tear retention devices. Diquafosol
is a unique agent for the treatment of dry eye in that it acts as a P2Y2
purinergic receptor agonist with the ability to activate this receptor on
the ocular surface and stimulate water, lipid, and mucin secretion. Diquafosol is metabolized by phosphodiesterases to UTP, UDP, UMP, and uridine. Diquafosol has been well tolerated in clinical trials, with side effects being local to the ocular surface.In addition,no serious ocular or systemic adverse drug reactions were found
during the clinical trials.
Inspire Pharmaceuticals (United States)
Enhancement of mucosal hydration in the treatment of chronic dry eye (P2Y2 receptor antagonist).
Diquafosol tetrasodium was approved in April 2010 as Diquas ® ophthalmic solution 3% for the
treatment of dry eye syndrome and launched in Japan by Santen Pharmaceuticals. Diquafosol
tetrasodium was originally discovered by Inspire Pharmaceuticals. In 2001, it was licensed to Santen
for co-development and commercialization in Asian countries, and co-developed in collaboration with
Allergan for the countries outside of Asia. In the U.S., diquafosol tetrasodium was submitted for a New Drug Application (NDA) as Prolacria ®(2% ophthalmic formulation) in June 2003. However, it is still
in Phase III clinical development for dry eye syndrome. Diquafosol tetrasodium, also known as INS-
365, is a P2Y2 receptor agonist, which activates P2Y2 receptor on the ocular surface, leading to
rehydration through activation of the fluid pump mechanism of the accessory lacrimal glands on the
conjunctival surface.
The large-scale synthesis route of diquafosol tetrasodium is described in
Scheme 4. Commercially available uridine 5?ˉ-diphosphate disodium salt (21) was transformed
into the corresponding tributylamine salt by ion exchange chromatography on Dowex 50 using Bu3NH+
phase, and then dimerized by means of CDI in DMF at 50 oC. The crude product was purified by
Sephadex DEAE column followed by ion exchange using a Dowex 50W resin in Na+ mode. The onepot
process provided diquafosol tetrasodium (IV) in 25% yield.
