Publication

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

De Leval, X., Ilies, M., Casini, A., Dogné, J-M., Scozzafava, A., Masini, E., Mincione, F., Starnotti, M. & Supuran, C. T., May-2004, In : Journal of Medicinal Chemistry. 47, 11, p. 2796-2804 9 p.

Research output: Contribution to journalArticleAcademicpeer-review

APA

De Leval, X., Ilies, M., Casini, A., Dogné, J-M., Scozzafava, A., Masini, E., ... Supuran, C. T. (2004). Carbonic anhydrase inhibitors: Synthesis and topical intraocular pressure lowering effects of fluorine-containing inhibitors devoid of enhanced reactivity. Journal of Medicinal Chemistry, 47(11), 2796-2804. https://doi.org/10.1021/jm031116j

Author

De Leval, X. ; Ilies, M. ; Casini, A. ; Dogné, J.-M. ; Scozzafava, A. ; Masini, E. ; Mincione, F. ; Starnotti, M. ; Supuran, C.T. / Carbonic anhydrase inhibitors : Synthesis and topical intraocular pressure lowering effects of fluorine-containing inhibitors devoid of enhanced reactivity. In: Journal of Medicinal Chemistry. 2004 ; Vol. 47, No. 11. pp. 2796-2804.

Harvard

De Leval, X, Ilies, M, Casini, A, Dogné, J-M, Scozzafava, A, Masini, E, Mincione, F, Starnotti, M & Supuran, CT 2004, 'Carbonic anhydrase inhibitors: Synthesis and topical intraocular pressure lowering effects of fluorine-containing inhibitors devoid of enhanced reactivity', Journal of Medicinal Chemistry, vol. 47, no. 11, pp. 2796-2804. https://doi.org/10.1021/jm031116j

Standard

Carbonic anhydrase inhibitors : Synthesis and topical intraocular pressure lowering effects of fluorine-containing inhibitors devoid of enhanced reactivity. / De Leval, X.; Ilies, M.; Casini, A.; Dogné, J.-M.; Scozzafava, A.; Masini, E.; Mincione, F.; Starnotti, M.; Supuran, C.T.

In: Journal of Medicinal Chemistry, Vol. 47, No. 11, 05.2004, p. 2796-2804.

Research output: Contribution to journalArticleAcademicpeer-review

Vancouver

De Leval X, Ilies M, Casini A, Dogné J-M, Scozzafava A, Masini E et al. Carbonic anhydrase inhibitors: Synthesis and topical intraocular pressure lowering effects of fluorine-containing inhibitors devoid of enhanced reactivity. Journal of Medicinal Chemistry. 2004 May;47(11):2796-2804. https://doi.org/10.1021/jm031116j


BibTeX

@article{d468885d822e43f8b32a085b0ce6eb65,
title = "Carbonic anhydrase inhibitors: Synthesis and topical intraocular pressure lowering effects of fluorine-containing inhibitors devoid of enhanced reactivity",
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.",
author = "{De Leval}, X. and M. Ilies and A. Casini and J.-M. Dogn{\'e} and A. Scozzafava and E. Masini and F. Mincione and M. Starnotti and C.T. Supuran",
note = "Cited By (since 1996):28 Export Date: 20 May 2014 Source: Scopus",
year = "2004",
month = "5",
doi = "10.1021/jm031116j",
language = "English",
volume = "47",
pages = "2796--2804",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "AMER CHEMICAL SOC",
number = "11",

}

RIS

TY - JOUR

T1 - Carbonic anhydrase inhibitors

T2 - Synthesis and topical intraocular pressure lowering effects of fluorine-containing inhibitors devoid of enhanced reactivity

AU - De Leval, X.

AU - Ilies, M.

AU - Casini, A.

AU - Dogné, J.-M.

AU - Scozzafava, A.

AU - Masini, E.

AU - Mincione, F.

AU - Starnotti, M.

AU - Supuran, C.T.

N1 - Cited By (since 1996):28 Export Date: 20 May 2014 Source: Scopus

PY - 2004/5

Y1 - 2004/5

N2 - 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.

AB - 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.

U2 - 10.1021/jm031116j

DO - 10.1021/jm031116j

M3 - Article

VL - 47

SP - 2796

EP - 2804

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 11

ER -

ID: 13320637