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Casey Kopczynski, Cheng-Wen Lin, Mitchell deLong, Jeffrey Yingling, Geoff Heintzelman, Jill Sturdivant, Bryan Sherman, Carmen Laethem, Thomas van Haarlem; IOP-lowering Efficacy And Tolerability Of AR-13324, A Dual Mechanism Kinase Inhibitor For The Treatment Of Glaucoma. Invest. Ophthalmol. Vis. Sci. 2012;53(14):5080.
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Inhibitors of Rho kinase (ROCK) lower intraocular pressure by increasing aqueous outflow through the trabecular meshwork (TM). We present a preclinical characterization of AR-13324, an inhibitor of both ROCK and the Norepinephrine Transporter (NET) that has been shown to lower IOP through a dual mechanism of action: increasing trabecular outflow and decreasing aqueous production.
A panel of compounds were designed, synthesized and screened for protein kinase inhibitory activity, including ROCK2 inhibition. The ability of compounds to induce specific morphological changes in cultured human and porcine TM cells was assessed by staining cells for actin and focal adhesions and imaging on an InCell 1000. Select compounds were tested for ocular hypotensive activity and tolerability in normotensive Dutch Belted rabbits and Formosan Rock monkeys. Test formulations were administered once-daily to one eye with the contralateral untreated eye serving as a control. Activity against NET was assessed in a competitive binding assay measuring inhibition of 3H-nisoxetine binding to human NET.
AR-13324 was identified as a potent inhibitor of ROCK2 (1.2 nM Ki) that induced changes in human and porcine TM cell morphology at low concentrations (56 nM and 212 nM EC50, respectively). It also demonstrated significant activity against human NET (410 nM Ki). In a 10-day rabbit study, mean IOP for untreated eyes ranged from 24.8 - 28.0 mm Hg. Treatment with 0.04% AR-13324 (n=6) produced maximal mean IOP reductions (p<0.001) at 4 hours post dosing that ranged from 5.7 mm Hg (22%) to 7.1 mm Hg (27%). Trace (+0.5) hyperemia (Draize scale 0 - 4) lasting 4-8 hours was initially observed with dosing but was largely absent after Day 8. In a 3-day monkey study, mean IOP for untreated eyes ranged from 19.8 - 20.5 mm Hg. Treatment with 0.04% AR-13324 (n=6) reduced mean IOP (p<0.001) on Day 3 by 7.5 mm Hg (37%), 7.2 mm Hg (36%) and 7.5 mm Hg (37%) at 4, 8 and 24 hours after dosing, respectively. There was no evidence of ocular irritation in monkeys.
AR-13324 produces large reductions in IOP with a long duration of action and is well tolerated in normotensive rabbits and monkeys. AR-13324 shows promise as a novel ocular hypotensive agent for the treatment of glaucoma. These data support once-daily administration of AR-13324 in a first-in-human clinical study.
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