Design, Synthesis, and Evaluation of NO-Donor Containing Carbonic Anhydrase Inhibitors To Lower Intraocular Pressure

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...

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Published inJournal of medicinal chemistry Vol. 58; no. 6; pp. 2821 - 2833
Main Authors Huang, Qinhua, Rui, Eugene Y, Cobbs, Morena, Dinh, Dac M, Gukasyan, Hovhannes J, Lafontaine, Jennifer A, Mehta, Saurabh, Patterson, Brian D, Rewolinski, David A, Richardson, Paul F, Edwards, Martin P
Format Journal Article
LanguageEnglish
Published WASHINGTON American Chemical Society 26.03.2015
Amer Chemical Soc
Subjects
Animals
Carbonic Anhydrase Inhibitors - chemistry
Carbonic Anhydrase Inhibitors - pharmacokinetics
Carbonic Anhydrase Inhibitors - pharmacology
Chemistry, Medicinal
Drug Design
Glaucoma - drug therapy
Intraocular Pressure - drug effects
Life Sciences & Biomedicine
Male
Nitric Oxide Donors - chemistry
Nitric Oxide Donors - pharmacokinetics
Nitric Oxide Donors - pharmacology
Pharmacology & Pharmacy
Rabbits
Science & Technology
Sulfonamides - chemistry
Sulfonamides - pharmacokinetics
Sulfonamides - pharmacology
Thiazines - chemistry
Thiazines - pharmacokinetics
Thiazines - pharmacology
Thiophenes - chemistry
Thiophenes - pharmacokinetics
Thiophenes - pharmacology
EYE
ENANTIOSELECTIVE SYNTHESIS
REDUCTION
LATANOPROST
OCULAR HYPERTENSION
ANTERIOR SEGMENT
NITRIC-OXIDE
ACTIVATORS
AGENTS
GLAUCOMA
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Summary: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).
Bibliography:ObjectType-Article-1
SourceType-Scholarly Journals-1
ObjectType-Feature-2
content type line 23
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b00043