Development of a highly promising drug candidate for the treatment of Glaucoma by reducing intraocul

Glaucoma is a group of conditions characterized by progressive damage to the optic-nerve which if left untreated can cause vision loss and blindness. It is the second leading cause of blindness globally. Although the exact cause of glaucoma is unknown, elevated intraocular pressure (IOP) is known to be the primary cause of the optic nerve damage. We developed a novel drug candidate, TG46, for reducing intraocular pressure and treating glaucoma based on a new mechanism, i.e. activation of P2Y6-receptor. We identified TG46 as the most potent and selective agonist of P2Y6 receptor currently known. In addition, TG46 is highly metabolically and chemically stable as evaluated at acidic pH, in the presence of nucleotide pyro-phosphatases and in blood serum. The therapeutic effect of the compound on IOP was evaluated by ocular administration of TG46 into normotense rabbits. TG46 reduced IOP by 45% and was more effective than any current glaucoma drug (e.g. Xalatan, Timolol, Pilocarpine, and Trusopt, which reduce IOP up to 33%). Furthermore, TG46 reduced IOP by 50% in hypertensive animals. TG46 is a highly safe drug candidate, more than current drugs. We explained the activity and selectivity of TG46 by a molecular model of P2Y6R we calculated based on the newly solved GPCR crystal structures as templates.

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