Abstract
Purpose :
We previously reported on the robust and long-lasting intraocular pressure (IOP)-lowering effects of NCX 1741, a NO-donating avanafil (PDE5 inhibitor) analog in models of ocular hypertension and glaucoma. Here we report on the IOP-lowering effects of NCX 1770, a newly designed single chemical entity optimized to release more NO and a different PDE5 inhibitory scaffold compared to NCX 1741 in naïve rabbits and a non-human primate model of ocular hypertension and glaucoma.
Methods :
Laser-induced unilateral ocular hypertensive non-human primates (OHT-monkeys, n=13 eye/group) and ocular normotensive New Zealand White rabbits (ONT-rabbits, n=8-15 eye/group) were used. Vehicle (phosphate buffer pH 6.0, Cremophor EL 5%, DMSO 0.3%, BAC 0.02%) and mirodenafil (PDE5 inhibitor) or NCX 1770 dissolved at equimolar doses in the vehicle were instilled (30μL to OHT-monkeys and 50μL to ONT-rabbits) in a masked, crossover fashion. IOP was determined by pneumatonometry prior to (baseline) and periodically post-dosing.
Results :
In ocular OHT-monkeys, mirodenafil (1% or 0.5µmol/eye/30µL) lowered IOP over time reaching a maximum at 3h post-dosing (IOP change vs baseline and vehicle, -5.0±2.1 mmHg). NCX 1770 (1.6% or 0.5µmol/eye/30µL) was more effective than mirodenafil at every time point with the greatest time-matched IOP change at 60min post-dosing (IOP change vs baseline and vs vehicle = -1.9±1.0 and -7.0±0.9 mmHg, for mirodenafil and NCX 1770, respectively). In ONT-rabbits NCX 1770 (1% or 0.5µmol/eye/50µL) effectively decreased the IOP over time (IOP change vs baseline and vs vehicle, -3.4±0.6, -3.8±0.5, -2.2±1.0, -1.9±0.8, -0.6±1.1 and -0.2±0.9 mmHg at 30, 60, 120, 180, 240 and 300min, respectively). These effects were greater than the time-matched IOP changes recorded for equimolar mirodenafil (0.6% or 0.5µmol/eye/50µL) doses (IOP change vs baseline and vs vehicle, -2.6±0.5, -2.5±0.8, -0.7±0.8, 0.3±0.8, -0.2±0.8 and -0.2±0.8 mmHg).
Conclusions :
NCX 1770 effectively lowers IOP in ONT-rabbits and OHT-monkeys. In both models the NCX 1770 elicited additional IOP-lowering effects compared to equimolar mirodenafil that is mechanistically attributed to the NO-donating moiety released from NCX 1770.
This is a 2020 ARVO Annual Meeting abstract.