Diquafosol tetrasodium: synthesis, uses and Mode of action

Introduction

Diquafosol tetrasodium is a P2Y2 purinergic receptor agonist that activates P2Y2 receptors on the ocular surface, leading to rehydration through activation of the fluid pump mechanism of the accessory lacrimal glands on the conjunctival surface. P2Y2 agonists are also potent mucin secretagogues and stimulate goblet-cell secretion of ocular mucins. This new ophthalmic solution has recently become commercially available in Japan for clinical use and holds promise for the effective treatment of dry eye syndrome[1].

Development

Diquafosol tetrasodium was approved in April 2010 as Diquas® ophthalmic solution 3% for treating dry eye syndrome and launched in Japan by Santen Pharmaceuticals. Diquafosol tetrasodium was initially 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 countries outside Asia. In the US, 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.

Synthesis

Commercially available uridine 5′-diphosphate disodium salt was transformed into the corresponding tributylamine salt by ion exchange chromatography on Dowex 50 using Bu3NH+ phase and then dimerized using CDI in DMF at 50 °C. The crude product was purified by Sephadex DEAE column followed by ion exchange using a Dowex 50W resin in Na+ mode. The one-pot process provided diquafosol tetrasodium (IV) with a 25% yield.

Mode of action

Diquafosol tetrasodium, a uridine 5′-triphosphate (UTP) analogue, is an agonist of the purinergic P2Y2 receptor. This receptor is a membrane protein encoded by the P2RY2 gene and belongs to the family of G-protein coupled receptors. It responds to extracellular purine and pyrimidine nucleotides, especially UTP and adenosine 5′-triphosphate (ATP), to promote diverse cellular physiological functions by eliciting Ca2+ release from the endoplasmic reticulum. P2Y2 receptors are found at several anterior eye sites, such as the corneal and conjunctival epithelia and conjunctival goblet cells. DQS stimulates the secretion of both water and mucins from cells into tears. Because of these pharmacological actions, ophthalmic solutions containing DQS have been approved as therapeutic options for dry eye disease in some Asian countries, including Japan, South Korea and China[2].

References

[1] K Kamiya. “Clinical evaluation of the additive effect of diquafosol tetrasodium on sodium hyaluronate monotherapy in patients with dry eye syndrome: a prospective, randomized, multicenter study.” Eye 26 10 (2012): 1363–1368.

[2] Ken-Ichi Endo, Koushi Fujisawa, Asuka Sakamoto. “Diquafosol tetrasodium elicits total cholesterol release from rabbit meibomian gland cells via P2Y2 purinergic receptor signalling.” ACS Applied Electronic Materials (2021): 6989.

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