title: Metabolism studies of a small-molecule tumor necrosis factor-alpha (TNF-α) inhibitor, UTL-5b (GBL-5b).
abstract: UTL-5b is an anti-inflammatory and anti-arthritic small-molecule tumor necrosis factor-alpha inhibitor and a structural analogue of the anti-arthritic drug, leflunomide. Leflunomide is known to be metabolized to teriflunomide, but the metabolites of UTL-5b have not been reported. The objective of this study was to investigate whether UTL-5b has a similar metabolic behavior as leflunomide. Preliminary studies showed that when exposed to microsomes in vitro with or without NADPH, UTL-5b disappeared within 30 min. To further investigate the microsomal metabolism, liquid chromatography-ultraviolet (LC-UV) and LC/tandem mass spectrometry (LC-MS/MS) were employed to, respectively, monitor the microsomal metabolites and identify the structure of the metabolites using LC-full scan MS and LC combined with multiple-ion monitoring MS. Fragmentation determination was analyzed by two types of scans: product ion scans and precursor ion scan. The in vitro microsomal treatment of UTL-5b resulted in two major metabolites: 5-methylisoxazole-3-carboxylic acid and 2-chloroaniline. Thus, the in vitro metabolic behavior of UTL-5b appears to be different from that of leflunomide in that the isoxazole ring is cleaved.
authors: Unitech Pharmaceuticals, Inc., Ann Arbor, MI 48108, USA. jshaw@21-cti.com
authors: Jiajiu
authors: J
authors: Shaw
authors: Brian
authors: B
authors: Shay
authors: Jack
authors: J
authors: Jiang
authors: Frederick
authors: F
authors: Valeriote
authors: Ben
authors: B
authors: Chen
mesh_terms: D000814:Aniline Compounds / Q000378:metabolism; D000818:Animals; D002853:Chromatography, Liquid / Q000379:methods*; D007555:Isoxazoles / Q000737:chemistry / Q000378:metabolism*; D000077339:Leflunomide; D051379:Mice; D008813:Mice, Inbred ICR; D008862:Microsomes, Liver / Q000378:metabolism*; D053719:Tandem Mass Spectrometry / Q000379:methods*; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D000814:Aniline Compounds; D007555:Isoxazoles; D014409:Tumor Necrosis Factor-alpha; C578477:UTL-5b; C024327:3-methyl-5-isoxazolecarboxylic acid; C025257:2-chloroaniline; D000077339:Leflunomide