title: Synthesis and biochemical evaluation of N-(4-phenylthiazol-2-yl)benzenesulfonamides as high-affinity inhibitors of kynurenine 3-hydroxylase.
abstract: 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 mumol/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 mumol/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.
authors.affiliation: Pharma Division, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Röver
authors.forename: A M
authors.initials: AM
authors.lastname: Cesura
authors.forename: P
authors.initials: P
authors.lastname: Huguenin
authors.forename: R
authors.initials: R
authors.lastname: Kettler
authors.forename: A
authors.initials: A
authors.lastname: Szente
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D005110:Extracellular Space / Q000737:chemistry; D005849:Gerbillinae; D007668:Kidney / Q000187:drug effects / Q000201:enzymology; D007700:Kinetics; D007736:Kynurenic Acid / Q000378:metabolism; D050601:Kynurenine 3-Monooxygenase; D008099:Liver / Q000187:drug effects / Q000201:enzymology; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D006899:Mixed Function Oxygenases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015394:Molecular Structure; D018696:Neuroprotective Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D051381:Rats; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000096926:Benzenesulfonamides
chemical_list: D004791:Enzyme Inhibitors; D007736:Kynurenic Acid; D050601:Kynurenine 3-Monooxygenase; D006899:Mixed Function Oxygenases; D018696:Neuroprotective Agents; D013449:Sulfonamides; D013844:Thiazoles; C110195:N-(4-phenylthiazol-2-yl)benzenesulfonamide; D000096926:Benzenesulfonamides; C110196:Ro 61-8048