Introduction to Ocular Hypertension and Glaucoma and an Overview of Drug Screening Funnels for Discovering and Characterizing New Intraocular Pressure-Reducing Compounds

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Many forms of glaucoma prevail in our aging population. However, all forms cause a characteristic optic nerve and retinal ganglion cell (RGC) degeneration, which results in visual impairment and can ultimately cause blindness. The most common types of glaucoma are open-angle glaucoma (OAG) and angle-closure glaucoma (ACG), which afflict over 75 million individuals worldwide. Both these types of glaucoma involve an abnormal accumulation of aqueous humor (AQH) in the anterior chamber of the eye. This raises the intraocular pressure (IOP) which radiates out to cause mechanical damage to tissues at the back of the eye. Whilst no cure is available, the elevated IOP (ocular hypertension; OHT) is treatable with topical ocularly instilled drugs that either slow down the production of AQH or open up the congested AQH outflow pathway, which involves digestion of accumulated extracellular matrix in and around the trabecular meshwork and/or the ciliary muscle bundles. Furthermore, surgery and/or implantation of AQH microshunts in the anterior chamber can alleviate the OHT. Due to its chronic nature, medicated eyedrops are usually the first-line treatments involving the use of prostaglandin/prostanoid FPand/or EP2-receptor agonists. Combination products are used if one drug fails to lower and control the elevated IOP. Drug discovery of new receptor- or enzyme-targeted molecules for OHT/glaucoma treatment is still warranted since existing drugs have several deficiencies and produce ocular and/or systemic side effects. This chapter addresses various elements of ocular hypotensive drug discovery and development.