Carbonic anhydrase inhibitors: synthesis and topical intraocular pressure lowering effects of fluorine-containing inhibitors devoid of enhanced reactivity

Xavier de Leval, Monica Ilies, Angela Casini, Jean-Michel Dogné, Andrea Scozzafava, Emanuela Masini, Francesco Mincione, Michele Starnotti, Claudiu T Supuran

Research output: Contribution to journalArticlepeer-review

Abstract

Polyfluorinated carbonic anhydrase inhibitors (CAIs) show very good inhibitory properties against carbonic anhydrase (CA) and excellent in vivo antiglaucoma properties after topical administration in rabbits. Still, the pentafluorinated compounds reported previously by this group (Scozzafava et al. J. Med. Chem. 2000, 43, 4542-4551) showed high reactivity with thiol groups of cysteine, glutathione, and presumably other proteins containing such moieties, which may lead to severe ocular side effects. Here, we report an approach for obtaining fluorinated CA inhibitors without the undesired enhanced reactivity. Thus, new compounds have been obtained by attaching moieties with reduced reactivity toward aromatic substitution reactions to the molecules of aromatic/heterocyclic sulfonamides possessing derivatizable amino moieties. The employed tails of the 2,3,5,6-tetrafluorobenzoyl, 2,3,5,6-tetrafluophenylsulfonyl, and pentafluorophenylureido types induced excellent CA inhibitory properties in the new reported sulfonamides, mainly against the isozymes involved in aqueous humor secretion, CA II and CA IV, whereas affinity for CA I was lower. Several low-nanomolar CA II inhibitors were detected, which did not react with cysteine or glutathione, in contrast to the corresponding perfluorinated compounds previously reported. These derivatives also showed a potent reduction of the intraocular pressure (IOP) in hypertensive rabbits, amounting to 13-21 mmHg at 1 h postadministration (compared to 5 mmHg obtained with dorzolamide, a clinically used drug), and the decreased IOP was maintained for 4-5 h after the administration. These compounds constitute valuable candidates for obtaining topically acting antiglaucoma CA inhibitors of a new generation, with enhanced efficacy, prolonged duration of action, and reduced side effects.
Original languageEnglish
Pages (from-to)2796-804
Number of pages9
JournalJournal of Medicinal Chemistry
Volume47
Issue number11
DOIs
Publication statusPublished - 20 May 2004

Keywords

  • Administration, Topical
  • Animals
  • Carbonic Anhydrase I
  • Carbonic Anhydrase II
  • Carbonic Anhydrase IV
  • Carbonic Anhydrase Inhibitors
  • Fluorine
  • Glaucoma
  • Heterocyclic Compounds
  • Intraocular Pressure
  • Rabbits
  • Structure-Activity Relationship
  • Sulfonamides

Fingerprint Dive into the research topics of 'Carbonic anhydrase inhibitors: synthesis and topical intraocular pressure lowering effects of fluorine-containing inhibitors devoid of enhanced reactivity'. Together they form a unique fingerprint.

Cite this