Carbonic anhydrase inhibitors: inhibition of isozymes I, II and IV with N-hydroxysulfonamides--a novel class of intraocular pressure lowering agents.
A series of N-hydroxy sulfonamides has been prepared by reaction of alkyl-, arylalkyl- and arylsulfonyl halides or sulfonic acid anhydrides with hydroxylamine. Structurally related inhibitors were also obtained from acyl chlorides and hydroxylamine, as well as by reaction of tosyl isocyanate with hydroxylamine, sulfamic acid and sulfamide. Inhibition of three carbonic anhydrase (CA) isozymes, hCA I, hCA II and bCA IV (h = human; b = bovine) with the prepared compounds has been investigated. Good inhibitors, as well as compounds with moderate activity against these isozymes were detected, depending on the R group to which the SO2NHOH or CONHOH moieties were attached. Susceptibility to inhibition was generally: hCA II > bCA IV >> hCA I. Some of the new inhibitors showed very good antiglaucoma action when administered directly into the eye in experimental animals, acting as more efficient intraocular pressure lowering agents as compared to the clinical drug dorzolamide. This constitutes an encouraging result for obtaining novel antiglaucoma drugs from this class of CA inhibitors.
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Università degli Studi, Institute of Ophthalmology, Firenze, Italia.
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Briganti
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Scozzafava
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Supuran
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D000081:Acetamides / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000737:chemistry / Q000494:pharmacology; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002256:Carbonic Anhydrases / Q000187:drug effects; D002417:Cattle; D005901:Glaucoma / Q000188:drug therapy; D006801:Humans; D006898:Hydroxylamines / Q000737:chemistry; D007429:Intraocular Pressure / Q000187:drug effects*; D007527:Isoenzymes; D008297:Male; D011817:Rabbits; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000737:chemistry / Q000494:pharmacology; D013451:Sulfonic Acids / Q000737:chemistry / Q000494:pharmacology; D013876:Thiophenes; D014105:Tosyl Compounds / Q000737:chemistry / Q000494:pharmacology; D005464:Fluorobenzenes; D005466:Fluorocarbons
D000081:Acetamides; D000959:Antihypertensive Agents; D002257:Carbonic Anhydrase Inhibitors; D002256:Carbonic Anhydrases; D006898:Hydroxylamines; D007527:Isoenzymes; D013449:Sulfonamides; D013451:Sulfonic Acids; D013876:Thiophenes; D014105:Tosyl Compounds; C116301:N-hydroxy-4-acetylaminophenylsulfonamide; C116302:N-hydroxypentafluorophenylsulfonamide; D005464:Fluorobenzenes; D005466:Fluorocarbons; C116300:O-(4-tosylamidocarbonyl)sulfamic acid; C062765:dorzolamide