RT Journal Article
SR Electronic
T1 Metabolism of LY654322, a Growth Hormone Secretagogue, to an Unusual Diimidazopyridine Metabolite
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 740
OP 749
DO 10.1124/dmd.110.037598
VO 39
IS 5
A1 Anthony G. Borel
A1 Timothy M. Jones
A1 Robert J. Barbuch
A1 David A. Jackson
A1 Palaniappan Kulanthaivel
A1 Edward Mattiuz
A1 Valentine J. Klimkowski
A1 William J. Wheeler
A1 Gregory A. Rener
YR 2011
UL http://dmd.aspetjournals.org/content/39/5/740.abstract
AB 2-Methylalanyl-N-{1-[(1R)-1-(4-fluorophenyl)-1-methyl-2-oxo-2-pyrrolidin-1-ylethyl]-1H-imidazol-4-yl}-5-phenyl-d-norvalinamide (LY654322) was rapidly cleared in rats and dogs by renal excretion of parent and metabolism (oxidative and hydrolytic). Among the metabolites identified in the urine of rats and dogs was M25, which was structurally unusual. Indeed, the characterization of M25 and investigation into its disposition relied on the convergence of diverse analytical methodologies. M25 eluted after the parent on reverse-phase chromatography with an MH+ at m/z 598 (parent + 35 Da). Given its increased lipophilicity and its mass difference compared with the parent, it was evident that M25 was not a phase 2 conjugate. Subsequent liquid chromatography with multiple-stage tandem mass spectrometry and accurate mass experiments identified the structure of M25 as having two replicates of the 1-(4-fluorophenyl)-1-methyl-2-oxo-2-pyrrolidinyl substructure flanking a central aromatic core of composition C7H3N5 that was refractory to fragmentation. Compared with the UV spectrum of the parent (λmax = 213 nm), M25 displayed a bathochromic shift (λmax = 311 nm), which substantiated extensive conjugation within the central core. Subsequent NMR analysis of M25 isolated from dog urine coupled with molecular modeling revealed the structure to be consistent with a diimidazopyridine core with two symmetrically substituted 1-(4-fluorophenyl)-1-methyl-2-oxo-2-pyrrolidinyl moieties. Using a structural analog with a chromophore similar to M25, LC-UV was used to quantitate M25 and determine its urinary disposition. The formation of M25 appears consistent with hydrolysis of LY654322 to an aminoimidazole, dimerization of the latter with the loss of NH3, C-formylation, and subsequent ring closure and aromatization with loss of H2O.