title: Mechanistic studies on a P450-mediated rearrangement of BMS-690514: conversion of a pyrrolotriazine to a hydroxypyridotriazine.
abstract: BMS-690514 ((3R,4R)-4-amino-1-((4-((3-methoxyphenyl)amino)pyrrolo[2,1-f][1,2,4] triazin-5-yl)methyl)-3-piperidinol) is an oral oncologic agent being developed for the treatment of patients with advanced nonsmall cell lung cancer and breast cancer. The compound is metabolized via multiple metabolic pathways, including P450-mediated oxidation at one of the carbons of its pyrrolotriazine group. Oxidation at this site results in the formation of two metabolites, M1 and M37. Mass spectrometric and NMR analysis revealed that M1 underwent an unusual structural change, where the pyrrolotriazine moiety rearranged to yield a hydroxypyridotriazine group. In contrast, the structure of the pyrrolotriazine moiety remained intact in M37. In vitro experiments with liver microsomes and deuterated or tritiated BMS-690514 containing the isotopic label on the carbon that underwent oxidation indicated that during the formation of M1, the isotope label was retained at the site of hydroxylation, while the label was lost during the formation of M37. On the basis of these results, a mechanism for the formation of M1 was proposed as follows: BMS-690514 was first oxidized by P450 enzymes either via epoxidation or an iron-oxo addition pathway to form a zwitterionic intermediate. This was followed by opening of the pyrrolotriazine ring to form an aldehyde intermediate, which could be partially trapped with methoxyamine. The aldehyde intermediate then reacted with the secondary amine of the methoxyaniline group in the molecule to form the pyridotriazine moiety of M1. This mechanism is consistent with the observed retention of the isotope label in M1. Metabolite M37 may be formed either via a common zwitterionic intermediate, shared with M1, or through a direct insertion pathway. In in vitro human liver microsome incubations, the abundance of M1 was higher than M37, suggesting that breaking of the carbon-nitrogen bond to generate the aldehyde intermediate, a process similar to N-dealkylation, was a preferred pathway.
authors.affiliation: Departments of Pharmaceutical Candidate Optimization and Radiochemistry, Bristol-Myers Squibb Research, Princeton, New Jersey 08543, United States.
authors.forename: Haizheng
authors.initials: H
authors.lastname: Hong
authors.forename: Janet
authors.initials: J
authors.lastname: Caceres-Cortes
authors.forename: Hong
authors.initials: H
authors.lastname: Su
authors.forename: Xiaohua
authors.initials: X
authors.lastname: Huang
authors.forename: Vikram
authors.initials: V
authors.lastname: Roongta
authors.forename: Samuel
authors.initials: S
authors.lastname: Bonacorsi
authors.forename: Yang
authors.initials: Y
authors.lastname: Hong
authors.forename: Yuan
authors.initials: Y
authors.lastname: Tian
authors.forename: Ramaswamy A
authors.initials: RA
authors.lastname: Iyer
authors.forename: W Griffith
authors.initials: WG
authors.lastname: Humphreys
authors.forename: Lisa J
authors.initials: LJ
authors.lastname: Christopher
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000378:metabolism*; D003577:Cytochrome P-450 Enzyme System / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D006900:Hydroxylation; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D008862:Microsomes, Liver / Q000201:enzymology; D010084:Oxidation-Reduction; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism*; D011758:Pyrroles / Q000737:chemistry / Q000378:metabolism*; D014227:Triazines / Q000737:chemistry* / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C552150:BMS-690514; D010880:Piperidines; D011758:Pyrroles; D014227:Triazines; D003577:Cytochrome P-450 Enzyme System