Ocular hypotensive activity of BOL-303259-X, a nitric oxide donating Prostaglandin F2α agonist, in preclinical models

A new approach to antiglaucoma drugs: carbonic anhydrase inhibitors with or without NO donating moieties. Mechanism of action and preliminary pharmacology

“…Although different forms of glaucoma are known, the most common condition is adult-onset open chamber-angle glaucoma ("open angle glaucoma" or OAG), which is age related and characterized by an open chamber angle, elevated IOP, a visual field defect and an area of pallor around the cupped optic nerve head, as well as constriction of blood flow through the vasculature [1][2][3] . Nitric oxide (NO), a radical gas produced by the enzyme nitric oxide synthase (NOS) is involved in aqueous humour outflow within the eye, local modulation of ocular blood flow, and retinal ganglion cells death by [4][5][6] . It has been observed that hypertensive glaucoma patients have a decreased NO/cGMP content in the aqueous humour 3 and that several classes of NO-donors decrease IOP in normal and pathological conditions [4][5][6][7] .…”

“…Nitric oxide (NO), a radical gas produced by the enzyme nitric oxide synthase (NOS) is involved in aqueous humour outflow within the eye, local modulation of ocular blood flow, and retinal ganglion cells death by [4][5][6] . It has been observed that hypertensive glaucoma patients have a decreased NO/cGMP content in the aqueous humour 3 and that several classes of NO-donors decrease IOP in normal and pathological conditions [4][5][6][7] . Sulfonamides acting as inhibitors of the zinc enzyme carbonic anhydrase (CA, EC 4.2.1.1) are clinically used as antiglaucoma agents for decades [8][9][10][11] .…”

Intraocular Pressure–Lowering Activity of NCX 470, a Novel Nitric Oxide–Donating Bimatoprost in Preclinical Models

“…The purpose of this study was to test this hypothesis in a head-to-head comparison of NCX 470 and bimatoprost at equimolar doses in three well-established animal models of glaucoma. Specifically, transiently ocular hypertensive New Zealand white rabbits (tOHT-rabbits) previously shown to respond to NO 17 and not as much to PGF2a agonists 13,18 were chosen to dissect the NO contribution from that of bimatoprost. Ocular normotensive dogs (ONT-dogs) and hypertensive nonhuman primates (OHTmonkeys) were instead selected as species sensitive to both PGF2a analogues and NO.…”

“…Ocular normotensive dogs (ONT-dogs) and hypertensive nonhuman primates (OHTmonkeys) were instead selected as species sensitive to both PGF2a analogues and NO. 18 Finally, we also monitored the concentrations of NCX 470 or bimatoprost, bimatoprost acid, and cGMP in ocular tissues following topical dosing with NCX 470 or bimatoprost in naïve pigmented Dutch Belted rabbits to ascertain potential differences in the absorption profile of the two compounds.…”

“…We and others have repeatedly reported that tOHT-rabbits are sensitive to most IOP-lowering agents including NO 17 but not to PGF2a agonists, 13,18,19 which makes this species ideal to dissect out the NO-mediated effects of NCX 470. Hypertonic saline injection (0.1 mL) into the vitreous body transiently increased IOP from 18.7 6 0.4 to 46.7 6 1.4 mm Hg within 30 minutes to then gradually return back to baseline over the following 5 hours (Fig.…”