title: Pharmacology of novel intraocular pressure-lowering targets that enhance conventional outflow facility: Pitfalls, promises and what lies ahead?
abstract: Intraocular pressure (IOP) lowering drugs that are approved for the treatment of glaucoma and ocular hypertension have limited activity on increasing aqueous humor movement through the trabecular meshwork and Schlemm's canal (TM/SC). The TM/SC complex is considered the conventional outflow pathway and is a primary site of increased resistance to aqueous humor outflow in glaucoma. Novel mechanisms that enhance conventional outflow have shown promise in IOP reduction via modulation of several pathways including Rho kinase, nitric oxide/soluble guanylate cyclase/cGMP, adenosine A1, prostaglandin EP4/cAMP, and potassium channels. The clinical translatability of these pharmacological modulators based on pre-clinical efficacy models is currently being explored. In addition, identification of pathways from GWAS and other studies involving transgenic rodent models with elevated/reduced IOP phenotypes have begun to yield additional insights into IOP regulation and serve as a source for the next generation of IOP lowering targets. Lastly, improvements in drug delivery technologies to enable sustained IOP reduction are also discussed.
authors.affiliation: Glaucoma Research - Ophthalmology, Novartis Institutes for Biomedical Research (NIBR), 22 Windsor Street, Cambridge, MA 02139, USA. Electronic address: ganesh.prasanna@novartis.com.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Prasanna
authors.affiliation: Glaucoma Research - Ophthalmology, Novartis Institutes for Biomedical Research (NIBR), 22 Windsor Street, Cambridge, MA 02139, USA.
authors.forename: Byron
authors.initials: B
authors.lastname: Li
authors.affiliation: Global Discovery Chemistry - Novartis Institutes for Biomedical Research (NIBR), 100 Technology Square, Cambridge, MA 02139, USA.
authors.forename: Muneto
authors.initials: M
authors.lastname: Mogi
authors.affiliation: Glaucoma Research - Ophthalmology, Novartis Institutes for Biomedical Research (NIBR), 22 Windsor Street, Cambridge, MA 02139, USA.
authors.forename: Dennis S
authors.initials: DS
authors.lastname: Rice
mesh_terms: D000818:Animals; D055808:Drug Discovery; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects*; D058990:Molecular Targeted Therapy / Q000379:methods*
keywords: Glaucoma; Intraocular pressure; Outflow; Pharmacology; Schlemm’s canal; Trabecular meshwork