Nitric Oxide (NO) plays an important role in modulating intraocular pressure (IOP), a major risk factor for glaucoma. Constitutive NOS are found in many ocular tissues including those regulating inflow and outflow. Administration of compounds stimulating the NO-cGMP pathway or overexpression of eNOS lead to increases of outflow resulting in IOP lowering.Currently, there are no IOP lowering drugs acting through the NO-cGMP pathway. Data suggests that NO-donors may decrease IOP through the conventional outflow route complementary to the uveoscleral pathway used by PGF 2a analogs. We designed new compounds targeting both NO donation and activation of PGF 2a (FP) receptors. Herein, I present synthetic efforts on latanoprost isopropylester (Xalatan) analogs where the isopropyl moiety was replaced with linkers bearing one or two nitrates. The compounds were tested in glaucoma models. BOL-303259-X showed potent IOP lowering in phase 2 studies. Nicox's partner Bausch + Lomb is advancing BOL-303259-X into phase 3.

Discovery of nitric oxide-donating prostaglandin F2α analogs for the treatment of glaucoma

245th National Meeting (2013)

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