Comparison of metabolism and toxicity to the structure of the anticancer agent sulofenur and related sulfonylureas.
The metabolic formation of p-chloroaniline from the oncolytic agent sulofenur [N-(5-indanesulfonyl)-N'-(4-chlorophenyl)urea, LY186641,] and from similar diaryl-substituted sulfonylureas, and its possible relevance to the compound's toxicity, was studied. In previous studies it was found that significant amounts of metabolites such as 2-amino-5-chlorophenyl sulfate (II), which is also a metabolite of p-chloroaniline, are formed from sulofenur in mice, rats, monkeys, and humans. The metabolism of N-(4-tolyl)-N'-(2-hydroxy-4-chlorophenyl)-urea (V) was studied, and V was not found to be an intermediate in the metabolic formation of II from the sulfonylurea N-(4-tolyl)-N'-(4-chlorophenyl)urea (LY181984, III). The amounts of this p-chloroaniline metabolite (II) formed in C3H mice from a series of diarylsulfonylureas were found to correlate with the compound's propensities to form methemoglobin, one notable toxicity of p-chloroaniline. This metabolism was also found to correlate with the structure of the arylsulfonyl moiety of the sulfonylurea. Other evidence supports the hypothesis that p-chloroaniline is directly formed by metabolism of sulfofenur and similar diarylsulfonylureas as well. Metabolic formation of p-chloroaniline thus appears to be a plausible explanation for the methemoglobinemia and anemia found to be dose-limiting toxicities of sulofenur in Phase I trials.
Ehlhardt
W J
WJ
Lilly Research Laboratories, Indianapolis, Indiana 46285.
Woodland
J M
JM
Worzalla
J F
JF
Bewley
J R
JR
Grindey
G B
GB
Todd
G C
GC
Toth
J E
JE
Howbert
J J
JJ
D000814:Aniline Compounds / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000633:toxicity*; D005260:Female; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008706:Methemoglobin / Q000032:analysis; D051379:Mice; D008809:Mice, Inbred C3H; D013329:Structure-Activity Relationship; D013453:Sulfonylurea Compounds / Q000737:chemistry / Q000378:metabolism / Q000633:toxicity*
D000814:Aniline Compounds; D000970:Antineoplastic Agents; D013453:Sulfonylurea Compounds; D008706:Methemoglobin; C058179:sulofenur; C004658:4-chloroaniline