y-39983 and Ocular-Hypertension

Topics: Administration, Topical; Adult; Aged; Antihypertensive Agents; Double-Blind Method; Female; Glaucoma, Open-Angle; Humans; Intraocular Pressure; Male; Middle Aged; Ocular Hypertension; Ophthalmic Solutions; Pyridines; rho-Associated Kinases; Tonometry, Ocular; Young Adult

To determine whether ROCK inhibition for the treatment of glaucoma can be improved by using novel, locally acting Rho kinase (ROCK) inhibitors, such as AMA0076, that lower IOP without inducing hyperemia.. On-target potency of AMA0076 was compared with other ROCK inhibitors (Y-27632 and Y-39983) and conversion of AMA0076 into its functionally inactive metabolite was evaluated in rabbit eye tissues. Human trabecular meshwork (HTM) cell morphology, actin filaments, and focal adhesion were studied in vitro after exposure to AMA0076. The effect of AMA0076 on IOP was investigated in normotensive rabbits and a new, acute hypertensive rabbit model. Intraocular pressure lowering efficacy of AMA0076 was compared with pharmacologic treatments. Hyperemia after single topical dosing of AMA0076 and Y-39983 was scored.. AMA0076 and Y-39983 showed similar on-target potency. AMA0076 was most stable in aqueous humor and converted into its metabolite in other eye tissues. Exposure of HTM cells to AMA0076 led to significant and reversible changes in cell shape and a decrease in actin stress fibers and focal adhesions. Both AMA0076 and Y-39983 provided an equivalent IOP control. Compared with latanoprost and bimatoprost, AMA0076 was more potent in preventing the IOP elevation in the acute hypertensive rabbit model. The degree of hyperemia was significantly lower in rabbits treated with AMA0076 then with Y-39983.. AMA0076 is a locally acting ROCK inhibitor that is able to induce altered cellular behavior of HTM cells. Administration of AMA0076 effectively reduces IOP in ocular normotensive and acute hypertensive rabbits without causing distinct hyperemia.

Topics: Actins; Amides; Animals; Antihypertensive Agents; Benzoates; Conjunctiva; Disease Models, Animal; Focal Adhesions; Hyperemia; Intraocular Pressure; Male; Ocular Hypertension; Protein Kinase Inhibitors; Pyridines; Rabbits; rho-Associated Kinases; Tonometry, Ocular; Trabecular Meshwork; Vinculin

We identified a new benzothiophene containing Rho kinase inhibitor scaffold in an ultra high-throughput enzymatic activity screen. SAR studies, driven by a novel label-free cellular impedance assay, were used to derive 39, which substantially reduced intraocular pressure in a monkey model of glaucoma-associated ocular hypertension.

Topics: Animals; Disease Models, Animal; Glaucoma; Haplorhini; HeLa Cells; Humans; Intraocular Pressure; Ocular Hypertension; Protein Kinase Inhibitors; rho-Associated Kinases; Thiophenes

The discovery of a pyrrolopyrimidine class of LIM-kinase 2 (LIMK2) inhibitors is reported. These LIMK2 inhibitors show good potency in enzymatic and cellular assays and good selectivity against ROCK. After topical dosing to the eye in a steroid induced mouse model of ocular hypertension, the compounds reduce intraocular pressure to baseline levels. The compounds also increase outflow facility in a pig eye perfusion assay. These results suggest LIMK2 may be an effective target for treating ocular hypertension and associated glaucoma.

Topics: Administration, Topical; Animals; Antihypertensive Agents; Glaucoma; Guanidines; In Vitro Techniques; Intraocular Pressure; Lim Kinases; Mice; Nitriles; Ocular Hypertension; Piperazines; Pyrimidines; Pyrroles; Structure-Activity Relationship; Swine; Urea