Identification of metabolites of the tryptase inhibitor CRA-9249: observation of a metabolite derived from an unexpected hydroxylation pathway.
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.
Yu
Walter
W
Department of Drug Metabolism and Pharmacokinetics, Celera Genomics, 180 Kimball Way, South San Francisco, CA 94080, USA.
Dener
Jeffrey M
JM
Dickman
Daniel A
DA
Grothaus
Paul
P
Ling
Yun
Y
Liu
Liang
L
Havel
Chris
C
Malesky
Kimberly
K
Mahajan
Tania
T
O'Brian
Colin
C
Shelton
Emma J
EJ
Sperandio
David
D
Tong
Zhiwei
Z
Yee
Robert
R
Mordenti
Joyce J
JJ
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
D001562:Benzimidazoles; C513208:CRA 9249; D004791:Enzyme Inhibitors; D012697:Serine Endopeptidases; C509223:Tpsab1 protein, rat; C509221:Tpsb2 protein, rat; D053802:Tryptases