title: 2H-Thieno[3,2-e]- and [2,3-e]-1,2-thiazine-6-sulfonamide 1,1-dioxides as ocular hypotensive agents: synthesis, carbonic anhydrase inhibition and evaluation in the rabbit.
abstract: Novel non-chiral 2H-thieno[3,2-e]- and [2,3-e]-1,2-thiazine-6-sulfonamide 1,1-dioxides were synthesized for evaluation as potential candidates for the treatment of glaucoma. All of the compounds prepared were potent high affinity inhibitors of human carbonic anhydrase II, Ki < 0.5 nM. Additionally, inhibition of recombinant human carbonic anhydrase IV was determined for selected compounds; these were shown to be moderate to potent inhibitors of this isozyme with IC50 values ranging from 4.25 to 73.6 nM. Of the compounds evaluated for their ability to lower intraocular pressure in naturally hypertensive Dutch-belted rabbits, 5a, 17a3, 17b1, 17b2, 17h2 and 17i1 showed significant efficacy (> 20% decrease) in this model following topical ocular administration.
authors.affiliation: Ophthalmic Products Research, Alcon Research, Ltd., Fort Worth, TX 76134, USA.
authors.forename: H H
authors.initials: HH
authors.lastname: Chen
authors.forename: S
authors.initials: S
authors.lastname: Gross
authors.forename: J
authors.initials: J
authors.lastname: Liao
authors.forename: M
authors.initials: M
authors.lastname: McLaughlin
authors.forename: T
authors.initials: T
authors.lastname: Dean
authors.forename: W S
authors.initials: WS
authors.lastname: Sly
authors.forename: J A
authors.initials: JA
authors.lastname: May
mesh_terms: D000818:Animals; D000959:Antihypertensive Agents / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D002257:Carbonic Anhydrase Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology* / Q000627:therapeutic use; D002256:Carbonic Anhydrases / Q000187:drug effects*; D004341:Drug Evaluation; D005901:Glaucoma / Q000188:drug therapy*; D006801:Humans; D007429:Intraocular Pressure / Q000187:drug effects; D009682:Magnetic Resonance Spectroscopy; D011817:Rabbits; D013449:Sulfonamides / Q000138:chemical synthesis / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D000959:Antihypertensive Agents; D002257:Carbonic Anhydrase Inhibitors; D013449:Sulfonamides; D002256:Carbonic Anhydrases