title: Metabolism and pharmacokinetics of JM6 in mice: JM6 is not a prodrug for Ro-61-8048.
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.
authors.affiliation: CHDI Management/CHDI Foundation, 300 Alexander Park, Suite 110, Princeton, NJ 08540, USA. maria.beconi@chdifoundation.org
authors.forename: Maria G
authors.initials: MG
authors.lastname: Beconi
authors.forename: Dawn
authors.initials: D
authors.lastname: Yates
authors.forename: Kathryn
authors.initials: K
authors.lastname: Lyons
authors.forename: Kim
authors.initials: K
authors.lastname: Matthews
authors.forename: Steve
authors.initials: S
authors.lastname: Clifton
authors.forename: Tania
authors.initials: T
authors.lastname: Mead
authors.forename: Michael
authors.initials: M
authors.lastname: Prime
authors.forename: Dirk
authors.initials: D
authors.lastname: Winkler
authors.forename: Catherine
authors.initials: C
authors.lastname: O'Connell
authors.forename: Daryl
authors.initials: D
authors.lastname: Walter
authors.forename: Leticia
authors.initials: L
authors.lastname: Toledo-Sherman
authors.forename: Ignacio
authors.initials: I
authors.lastname: Munoz-Sanjuan
authors.forename: Celia
authors.initials: C
authors.lastname: Dominguez
mesh_terms: D000818:Animals; D019540:Area Under Curve; D002460:Cell Line; D004285:Dogs; D022781:Hepatocytes / Q000201:enzymology / Q000378:metabolism; D006801:Humans; D061985:Madin Darby Canine Kidney Cells; D008297:Male; D050216:Metabolic Detoxication, Phase I; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000201:enzymology / Q000378:metabolism; D011355:Prodrugs / Q000493:pharmacokinetics*; D051381:Rats; D013449:Sulfonamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D013844:Thiazoles / Q000008:administration & dosage / Q000493:pharmacokinetics*
chemical_list: C560311:2-(3,4-dimethoxybenzenesulfonylamino)-4-(3-nitrophenyl)-5-(piperidin-1-yl)methylthiazole; D011355:Prodrugs; C110196:Ro 61-8048; D013449:Sulfonamides; D013844:Thiazoles