HL3501, a Novel Selective A3 Adenosine Receptor Antagonist, Lowers Intraocular Pressure (IOP) in Animal Glaucoma Models

Purpose: The A3 adenosine receptor (A3AR) is a known therapeutic target for glaucoma treatment. In this study, we developed HL3501 and examined its selectivity profile and in vitro and in vivo effects. Methods: For the rabbit model, intraocular pressure (IOP) was increased by laser photo coagulation of the trabecular meshwork (TM). The rabbits were then topically treated with HL3501, latanoprost, timolol, or vehicle for 3 weeks. For the mouse model, HL3501, latanoprost, or vehicle was administered following induced IOP elevation by dexamethasone (Dex). The IOP of all rabbits and mice was measured. Electroretinography was performed on both eyes of dark-adapted anesthetized mice on days 0 and 21. The mice's eyes were enucleated at the end of the treatment for immunofluorescence staining. Results: HL3501 was highly specific to the A3AR and inhibitory of A3AR function. In the rabbit glaucoma model, HL3501 and latanoprost significantly decreased the IOP. In the Dex-treated mouse model, HL3501 and latanoprost significantly decreased the IOP and increased the b-wave amplitude as compared with the vehicle treatment. HL3501 and latanoprost also inhibited fibronectin and alpha-smooth muscle actin expression induced by Dex treatment. Conclusions: HL3501 had effects similar to those of latanoprost in reducing ocular hypertension in animal models. HL3501 could be used as a novel approach to treat glaucoma. Translational Relevance: HL3501 is a novel preclinical compound targeting the A3 adenosine receptor, which may also be a new treatment option to fill the unmet needs of many glaucoma patients.