Carbonic Anhydrase Inhibitors. The Mitochondrial Isozyme VB as a New Target for Sulfonamide and Sulfamate Inhibitors

• Published in: Journal of medicinal chemistry 2005-12, Vol.48 (24), p.7860-7866
• Main Authors: Nishimori, Isao, Vullo, Daniela, Innocenti, Alessio, Scozzafava, Andrea, Mastrolorenzo, Antonio, Supuran, Claudiu T
• Format: Article
• Language: English
• Subjects: Amino Acid Sequence; Biological and medical sciences; Carbonic Anhydrase Inhibitors - chemistry; Carbonic Anhydrase V - chemistry; Carbonic Anhydrase V - genetics; Carbonic Anhydrase V - isolation & purification; Catalysis; Cloning, Molecular; General and cellular metabolism. Vitamins; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - chemistry; Kinetics; Medical sciences; Mitochondria - enzymology; Molecular Sequence Data; Pharmacology. Drug treatments; Structure-Activity Relationship; Sulfonamides - chemistry; Sulfonic Acids - chemistry
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm050483n

A lately discovered carbonic anhydrase (hCA, EC 4.2.1.1), the mitochondrial hCA VB, was cloned, expressed, and purified. Kinetic parameters proved it to be 3.37 times more effective than hCA VA as a catalyst for the physiological reaction, with k cat = 9.5 × 105 s-1 and k cat/K M = 9.8 × 107 M-1 s-1, being second only to hCA II among the 16 isoforms presently known in humans. We investigated the inhibition of hCA VB with a library of sulfonamides/sulfamates, some of which are clinically used compounds. Benzenesulfonamides were ineffective inhibitors, whereas derivatives bearing 4-amino, 4-hydrazino, 4-methyl, 4-carboxy moieties or halogenated sulfanilamides were more effective (K i's of 1.56−4.3 μM). Among the 10 clinically used compounds, acetazolamide, benzolamide, topiramate, and indisulam showed effective inhibitory activity (K i's of 18−62 nM). Three compounds showed better activity against hCA VB over hCA II, among which were sulpiride and ethoxzolamide, which were 2 times more effective inhibitors of the mitochondrial over the cytosolic isozyme. hCA VB is a druggable target and some of its inhibitors may lead to the development of novel antiobesity therapies.