Abstract
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.
MeSH terms
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Administration, Topical
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Animals
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Antihypertensive Agents / chemical synthesis*
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Antihypertensive Agents / chemistry
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Antihypertensive Agents / pharmacology
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Glaucoma / drug therapy
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Glaucoma / physiopathology
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Guanidines / chemical synthesis
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Guanidines / chemistry
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Guanidines / pharmacology
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In Vitro Techniques
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Intraocular Pressure / drug effects
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Lim Kinases / antagonists & inhibitors*
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Mice
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Nitriles / chemical synthesis
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Nitriles / chemistry
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Nitriles / pharmacology
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Ocular Hypertension / chemically induced
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Ocular Hypertension / drug therapy*
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Ocular Hypertension / physiopathology
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Piperazines / chemical synthesis
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Piperazines / chemistry
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Piperazines / pharmacology
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Pyrimidines / chemical synthesis*
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Pyrimidines / chemistry
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Pyrimidines / pharmacology
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Pyrroles / chemical synthesis*
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Pyrroles / chemistry
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Pyrroles / pharmacology
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Structure-Activity Relationship
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Swine
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Urea / analogs & derivatives
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Urea / chemical synthesis
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Urea / chemistry
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Urea / pharmacology
Substances
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Antihypertensive Agents
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Guanidines
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Nitriles
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Piperazines
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Pyrimidines
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Pyrroles
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Urea
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Lim Kinases
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Limk2 protein, mouse