Title :

Design, solid-phase synthesis, and biological evaluation of novel 1,5-diarylpyrrole-3-carboxamides as carbonic anhydrase IX inhibitors

Author(s) :

Gluszok, Sebastien [Auteur]
Frederick, Raphael [Auteur]
Foulon, Catherine [Auteur]
Klupsch, Frederique [Auteur]
Supuran, Claudiu T [Auteur]
Vullo, Daniela [Auteur]
Scozzafava, Andrea [Auteur]
Goossens, Jean-Francois [Auteur]
Masereel, Bernard [Auteur]
Depreux, Patrick [Auteur]
Goossens, Laurence [Auteur]

Journal title :

Bioorganic & medicinal chemistry

Abbreviated title :

Bioorg. Med. Chem.

Volume number :

18

Pages :

7392-7401

Publication date :

2010-11-01

ISSN :

0968-0896

English keyword(s) :

Carbonic anhydrase
Pyrrole
Molecular modeling
Sulfonamide
Lipophilicity

HAL domain(s) :

Sciences du Vivant [q-bio]

English abstract : [en]

Following previous studies we herein report the synthesis and the pharmacological evaluation of a new class of human carbonic anhydrase (hCA) inhibitors, 1,5-diarylpyrrole-3-carboxamides prepared by a solid-phase strategy ...
Show more >Following previous studies we herein report the synthesis and the pharmacological evaluation of a new class of human carbonic anhydrase (hCA) inhibitors, 1,5-diarylpyrrole-3-carboxamides prepared by a solid-phase strategy involving a PS(HOBt) resin. A molecular modeling study was conducted in order to simulate the binding mode of this new family of enzyme inhibitors within the active site of hCA IX. This study revealed that the 3-position of the pyrrole was opened to the solvent, so we introduced an amino side-chain, protonated at physiological pH both to enhance the aqueous solubility and to decrease the cell membrane penetration. This strategy consisted of preparing membrane-impermeant inhibitors that may selectively target the tumor-associated hCA IX. Physico-chemical characterizations including aqueous solubility and lipophilic parameters are described. Pharmacological studies revealed high hCA IX inhibitory potency in the nanomolar range. Some compounds are selective for hCA IX displaying hCA I/hCA IX and hCA II/hCA IX ratios higher than 20 and 5, respectively.Show less >

Audience :

Internationale

Popular science :

Non

Administrative institution(s) :

CHU Lille
Inserm
Université de Lille

Collections :

• Groupe de Recherche sur les formes Injectables et les Technologies Associées (GRITA) - EA 7365
• Lille Inflammation Research International Center (LIRIC) - U995

Research team(s) :

Therapeutic innovation targetting inflammation

Submission date :

2019-05-17T13:08:45Z