AMA0076, a novel, locally acting Rho kinase inhibitor, potently lowers intraocular pressure in New Zealand white rabbits with minimal hyperemia.
OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
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.
The Laboratory of Ophthalmology, KU Leuven, Leuven, Belgium.
Sarah
S
Van de Velde
Tine
T
Van Bergen
Davine
D
Sijnave
Karolien
K
Hollanders
Karolien
K
Castermans
Olivier
O
Defert
Dirk
D
Leysen
Evelien
E
Vandewalle
Lieve
L
Moons
Ingeborg
I
Stalmans
D000199:Actins / Q000378:metabolism; D000577:Amides / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D001565:Benzoates / Q000009:adverse effects / Q000627:therapeutic use*; D003228:Conjunctiva / Q000098:blood supply*; D004195:Disease Models, Animal; D022001:Focal Adhesions / Q000378:metabolism; D006940:Hyperemia / Q000139:chemically induced*; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D009798:Ocular Hypertension / Q000188:drug therapy* / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology; D011817:Rabbits; D014065:Tonometry, Ocular; D014129:Trabecular Meshwork / Q000187:drug effects / Q000378:metabolism; D016596:Vinculin / Q000378:metabolism; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors*
D000199:Actins; D000577:Amides; D000959:Antihypertensive Agents; D001565:Benzoates; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C520365:Y-39983; D016596:Vinculin; C108830:Y 27632; D054460:rho-Associated Kinases
IOP lowering; ROCK inhibitors; glaucoma