Abstract
The antiglaucoma drugs dorzolamide (1) and brinzolamide (2) lower intraocular pressure (IOP) by inhibiting the carbonic anhydrase (CA) enzyme to reduce aqueous humor production. The introduction of a nitric oxide (NO) donor into the alkyl side chain of dorzolamide (1) and brinzolamide (2) has led to the discovery of NO-dorzolamide 3a and NO-brinzolamide 4a, which could lower IOP through two mechanisms: CA inhibition to decrease aqueous humor secretion (reduce inflow) and NO release to increase aqueous humor drainage (increase outflow). Compounds 3a and 4a have shown improved efficacy of lowering IOP in both rabbits and monkeys compared to brinzolamide (2).
MeSH terms
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Animals
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Carbonic Anhydrase Inhibitors / chemistry*
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Carbonic Anhydrase Inhibitors / pharmacokinetics
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Carbonic Anhydrase Inhibitors / pharmacology
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Drug Design
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Glaucoma / drug therapy
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Intraocular Pressure / drug effects*
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Male
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Nitric Oxide Donors / chemistry*
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Nitric Oxide Donors / pharmacokinetics
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Nitric Oxide Donors / pharmacology
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Rabbits
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Sulfonamides / chemistry*
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Sulfonamides / pharmacokinetics
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Sulfonamides / pharmacology
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Thiazines / chemistry*
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Thiazines / pharmacokinetics
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Thiazines / pharmacology
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Thiophenes / chemistry*
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Thiophenes / pharmacokinetics
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Thiophenes / pharmacology
Substances
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Carbonic Anhydrase Inhibitors
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Nitric Oxide Donors
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Sulfonamides
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Thiazines
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Thiophenes
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brinzolamide
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dorzolamide