title: Identification of metabolites of the tryptase inhibitor CRA-9249: observation of a metabolite derived from an unexpected hydroxylation pathway.
abstract: The metabolites of the tryptase inhibitor CRA-9249 were identified after exposure to liver microsomes. CRA-9249 was found to be degraded rapidly in liver microsomes from rabbit, dog, cynomolgus monkey, and human, and less rapidly in microsomes from rat. The key metabolites included cleavage of an aryl ether, in addition to an unexpected hydroxylation of the amide side chain adjacent to the amide nitrogen. The chemical structures of both metabolites were confirmed by synthesis and comparison to material isolated from the liver microsomes. Several suspected hydroxylated metabolites were also synthesized and analyzed as part of the structure identification process.
authors.affiliation: Department of Drug Metabolism and Pharmacokinetics, Celera Genomics, 180 Kimball Way, South San Francisco, CA 94080, USA.
authors.forename: Walter
authors.initials: W
authors.lastname: Yu
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Dener
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Dickman
authors.forename: Paul
authors.initials: P
authors.lastname: Grothaus
authors.forename: Yun
authors.initials: Y
authors.lastname: Ling
authors.forename: Liang
authors.initials: L
authors.lastname: Liu
authors.forename: Chris
authors.initials: C
authors.lastname: Havel
authors.forename: Kimberly
authors.initials: K
authors.lastname: Malesky
authors.forename: Tania
authors.initials: T
authors.lastname: Mahajan
authors.forename: Colin
authors.initials: C
authors.lastname: O'Brian
authors.forename: Emma J
authors.initials: EJ
authors.lastname: Shelton
authors.forename: David
authors.initials: D
authors.lastname: Sperandio
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Tong
authors.forename: Robert
authors.initials: R
authors.lastname: Yee
authors.forename: Joyce J
authors.initials: JJ
authors.lastname: Mordenti
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000378:metabolism*; D002851:Chromatography, High Pressure Liquid; D004285:Dogs; D004791:Enzyme Inhibitors / Q000378:metabolism*; D006900:Hydroxylation; D008252:Macaca fascicularis; D009682:Magnetic Resonance Spectroscopy; D051381:Rats; D012697:Serine Endopeptidases / Q000187:drug effects*; D053802:Tryptases
chemical_list: D001562:Benzimidazoles; C513208:CRA 9249; D004791:Enzyme Inhibitors; D012697:Serine Endopeptidases; C509223:Tpsab1 protein, rat; C509221:Tpsb2 protein, rat; D053802:Tryptases