2,7-Disubstituted-pyrrolotriazine kinase inhibitors with an unusually high degree of reactive metabolite formation.
There are numerous published studies establishing a link between reactive metabolite formation and toxicity of various drugs. Although the correlation between idiosyncratic reactions and reactive metabolite formation is not 1:1, the association between the two is such that many pharmaceutical companies now monitor for reactive metabolites as a standard part of drug candidate testing and selection. The most common method involves in vitro human microsomal incubations in the presence of a thiol trapping agent, such as glutathione (GSH), followed by LC/MS analysis. In this study, we describe several 2,7-disubstituted-pyrrolotriazine analogues that are extremely potent reactive metabolite precursors. Utilizing a UPLC/UV/MS method, unprecedented levels of GSH adducts were measured that are 5-10 times higher than previously reported for high reactive metabolite-forming compounds such as clozapine and troglitazone.
Worldwide Development, Cephalon Inc., West Chester, Pennsylvania 19380, USA. kwellskn@cephalon.com
Kevin J
KJ
Wells-Knecht
Gregory R
GR
Ott
Mangeng
M
Cheng
Gregory J
GJ
Wells
Henry J
HJ
Breslin
Diane E
DE
Gingrich
Linda
L
Weinberg
Eugen F
EF
Mesaros
Zeqi
Z
Huang
Mehran
M
Yazdanian
Mark A
MA
Ator
Lisa D
LD
Aimone
Kelli
K
Zeigler
Bruce D
BD
Dorsey
D000818:Animals; D001646:Bile / Q000737:chemistry; D001711:Biotransformation; D002626:Chemistry, Pharmaceutical; D002839:Chromans / Q000378:metabolism; D002851:Chromatography, High Pressure Liquid; D002853:Chromatography, Liquid; D003024:Clozapine / Q000378:metabolism; D004285:Dogs; D005978:Glutathione / Q000378:metabolism*; D000882:Haplorhini; D006801:Humans; D051379:Mice; D008862:Microsomes, Liver / Q000201:enzymology*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D011494:Protein Kinases / Q000378:metabolism; D011758:Pyrroles / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D051381:Rats; D021241:Spectrometry, Mass, Electrospray Ionization; D013438:Sulfhydryl Compounds / Q000378:metabolism; D045162:Thiazolidinediones / Q000378:metabolism; D014227:Triazines / Q000138:chemical synthesis / Q000378:metabolism* / Q000493:pharmacokinetics / Q000652:urine; D000077288:Troglitazone
D002839:Chromans; D047428:Protein Kinase Inhibitors; D011758:Pyrroles; D013438:Sulfhydryl Compounds; D045162:Thiazolidinediones; D014227:Triazines; D011494:Protein Kinases; D005978:Glutathione; D000077288:Troglitazone; D003024:Clozapine