title: Acetazolamide-like carbonic anhydrase inhibitors with topical ocular hypotensive activity.
abstract: New carbonic anhydrase (EC 4.2.1.1) inhibitors were synthesized as potential drugs for the topical treatment of glaucoma. They were obtained by substituting the acetyl group of acetazolamide and methazolamide with bicarboxylic acids of different chain length (C4-C6). The terminal carboxyl was either kept free or esterified with alcohols of different size (C1-C12). A gamma-aminovaleric derivative was also prepared. All compounds proved active as carbonic anhydrase inhibitors in vitro, with an average IC50 of about 0.5 microM. Some proved also to be topically active in vivo in lowering the artificially elevated intraocular pressure in rabbits. The most active compound, carrying a succinic acid side chain, is the most soluble in aqueous buffers. Its duration of action is about 8 h and it is under evaluation as a topical antiglaucoma drug. It is hypothesized that the duration of action could be longer in compounds having both the same high water solubility and partition coefficient.
authors.affiliation: Istituto Chimico Internazionale Dr. G. Rende, Roma, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Antonaroli
authors.forename: A
authors.initials: A
authors.lastname: Bianco
authors.forename: M
authors.initials: M
authors.lastname: Brufani
authors.forename: L
authors.initials: L
authors.lastname: Cellai
authors.forename: G
authors.initials: G
authors.lastname: Lo Baido
authors.forename: E
authors.initials: E
authors.lastname: Potier
authors.forename: L
authors.initials: L
authors.lastname: Bonomi
authors.forename: S
authors.initials: S
authors.lastname: Perfetti
authors.forename: A I
authors.initials: AI
authors.lastname: Fiaschi
authors.forename: G
authors.initials: G
authors.lastname: Segre
mesh_terms: D000086:Acetazolamide / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000287:Administration, Topical; D000818:Animals; D002257:Carbonic Anhydrase Inhibitors / Q000008:administration & dosage / Q000737:chemistry / Q000494:pharmacology*; D005901:Glaucoma / Q000188:drug therapy; D007429:Intraocular Pressure / Q000187:drug effects*; D008297:Male; D008704:Methazolamide / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D011817:Rabbits; D013329:Structure-Activity Relationship
chemical_list: D002257:Carbonic Anhydrase Inhibitors; D000086:Acetazolamide; D008704:Methazolamide