Abstract
Understanding whether regulation of tryptophan metabolites can ameliorate neurodegeneration is of high interest to investigators. A recent publication describes 3,4-dimethoxy-N-(4-(3-nitrophenyl)-5-(piperidin-1-ylmethyl)thiazol-2-yl)benzenesulfonamide (JM6) as a novel prodrug for the kynurenine 3-monooxygenase (KMO) inhibitor 3,4-dimethoxy-N-(4-(3-nitrophenyl)thiazol-2-yl)benzenesulfonamide (Ro-61-8048) that elicits therapeutic effects in mouse models of Huntington's and Alzheimer's diseases (Cell 145:863–874, 2011). Our evaluation of the metabolism and pharmacokinetics of JM6 and Ro-61-8048 indicate instead that Ro-61-8048 concentrations in mouse plasma after JM6 administration originate from a Ro-61-8048 impurity (<0.1%) in JM6. After a 0.05 mg/kg Ro-61-8048 oral dose alone or coadministered with 10 mg/kg JM6 to mice, the Ro-61-8048 areas under the concentration-time curves (AUCs) from 0 to infinity were similar (4300 and 4900 nM × h, respectively), indicating no detectable contributions of JM6 metabolism to the Ro-61-8048 AUCs. JM6 was stable in incubations under acidic conditions and Ro-61-8048 was not a product of JM6 metabolism in vitro (plasma, blood, or hepatic models). Species differences in the quantitative rate of oxidative metabolism indicate that major circulating JM6 metabolite(s) in mice are unlikely to be major in humans: JM6 is rapidly metabolized via the piperidyl moiety in mouse (forming an iminium ion reactive intermediate) but is slowly metabolized in human (in vitro), primarily via O-dealkylation at the phenyl ring. Our data indicate that JM6 is not a prodrug for Ro-61-8048 and is not a potent KMO inhibitor.
Footnotes
Competing Interests Statement: CHDI Foundation is a privately funded not-for-profit biomedical research organization exclusively dedicated to discovering and developing therapeutics that slow the progression of Huntington's disease. CHDI Foundation conducts research in a number of different ways; for the purposes of this article, all research was conceptualized, planned, and directed by CHDI scientific staff and conducted at the contract research organizations BioFocus, Saretius, Evotec, and Albany Molecular Research Inc. (AMRI).
Article, publication date, and citation information can be found at http://dmd.aspetjournals.org.
↵ The online version of this article (available at http://dmd.aspetjournals.org) contains supplemental material.
ABBREVIATIONS:
- HD
- Huntington's disease
- KMO
- kynurenine 3-monooxygenase
- JM6
- 3,4-dimethoxy-N-(4-(3-nitrophenyl)-5-(piperidin-1-ylmethyl)thiazol-2-yl)benzenesulfonamide
- Ro-61-8048
- 3,4-dimethoxy-N-(4-(3-nitrophenyl)thiazol-2-yl)benzenesulfonamide
- P450
- cytochrome P450
- DMSO
- dimethyl sulfoxide
- IS
- internal standard
- LC
- liquid chromatography
- MS/MS
- tandem mass spectrometry
- UPLC
- ultra-performance liquid chromatography
- MRM
- multiple reaction monitoring
- LLOQ
- lower limit of quantitation
- AUC
- area under the concentration versus time curve
- AUCN
- dose-normalized AUC
- MDCK
- Madin-Darby canine kidney
- MDR1
- multidrug-resistant protein 1
- WT
- wild type
- A
- apical
- B
- basolateral
- MS
- mass spectrometer
- HPLC
- high-performance liquid chromatography
- KYN
- kynurenine.
- Received April 28, 2012.
- Accepted August 31, 2012.
- Copyright © 2012 by The American Society for Pharmacology and Experimental Therapeutics
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