Synthesis and Biochemical Evaluation of N-(4-Phenylthiazol-2-yl)benzenesulfonamides as High-Affinity Inhibitors of Kynurenine 3-Hydroxylase

• Published in: Journal of medicinal chemistry Vol. 40; no. 26; pp. 4378 - 4385
• Main Authors: Röver, Stephan, Cesura, Andrea M, Huguenin, Philipp, Kettler, Rolf, Szente, Andre
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 19.12.1997; Amer Chemical Soc
• Subjects: Animals; Biological and medical sciences; Brain - drug effects; Brain - enzymology; Brain - metabolism; Chemistry, Medicinal; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Extracellular Space - chemistry; Gerbillinae; Kidney - drug effects; Kidney - enzymology; Kinetics; Kynurenic Acid - metabolism; Kynurenine 3-Monooxygenase; Life Sciences & Biomedicine; Liver - drug effects; Liver - enzymology; Medical sciences; Mitochondria - drug effects; Mitochondria - metabolism; Mixed Function Oxygenases - antagonists & inhibitors; Mixed Function Oxygenases - metabolism; Molecular Structure; Neuropharmacology; Neuroprotective agent; Neuroprotective Agents - chemical synthesis; Neuroprotective Agents - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Rats; Science & Technology; Structure-Activity Relationship; Sulfonamides - chemical synthesis; Sulfonamides - chemistry; Sulfonamides - pharmacology; Thiazoles - chemical synthesis; Thiazoles - chemistry; Thiazoles - pharmacology; EXCITOTOXICITY; NEUROTOXIN QUINOLINIC ACID; METABOLISM; PATHWAY; INJURY; MICE; CONVERT L-TRYPTOPHAN; RELEASE; RECEPTORS; BRAIN; Sulfonamide; Rat; Enzyme; Thiazole derivatives; Rodentia; Benzene derivatives; Oral administration; Enzyme inhibitor; Neuroprotective agent; In vitro; Kidney; In vivo; Vertebrata; Mammalia; Ex vivo; Structure activity relation; Animal; Kynurenine 3-monooxygenase; Oxidoreductases; Chemical synthesis; Gerbil
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970467t

In this paper we describe the synthesis, structure−activity relationship (SAR), and biochemical characterization of N-(4-phenylthiazol-2-yl)benzenesulfonamides as inhibitors of kynurenine 3-hydroxylase. The compounds 3,4-dimethoxy-N-[4-(3-nitrophenyl)thiazol-2-yl]benzenesulfonamide 16 (IC50 = 37 nM, Ro-61-8048) and 4-amino-N-[4-[2-fluoro-5-(trifluoromethyl)phenyl]thiazol-2-yl]benzenesulfonamide 20 (IC50 = 19 nM) were found to be high-affinity inhibitors of this enzyme in vitro. In addition, both compounds blocked rat and gerbil kynurenine 3-hydroxylase after oral administration, with ED50's in the 3−5 μmol/kg range in gerbil brain. In a microdialysis experiment in rats, 16 dose dependently increased kynurenic acid concentration in the extracellular hippocampal fluid. A dose of 100 μmol/kg po led to a 7.5-fold increase in kynurenic acid outflow. These new compounds should allow detailed investigation of the pathophysiological role of the kynurenine pathway after neuronal injury.