RT Journal Article
SR Electronic
T1 BIOACTIVATION OF THE 3-AMINO-6-CHLOROPYRAZINONE RING IN A THROMBIN INHIBITOR LEADS TO NOVEL DIHYDRO-IMIDAZOLE AND IMIDAZOLIDINE DERIVATIVES: STRUCTURES AND MECHANISM USING <sup>13</sup>C-LABELS, MASS SPECTROMETRY, AND NMR
JF Drug Metabolism and Disposition
JO Drug Metab Dispos
FD American Society for Pharmacology and Experimental Therapeutics
SP 1437
OP 1447
DO 10.1124/dmd.31.11.1437
VO 31
IS 11
A1 Raju Subramanian
A1 Charles C. Lin
A1 Jonathan Z. Ho
A1 Steven M. Pitzenberger
A1 Maria V. Silva-Elipe
A1 Christopher R. Gibson
A1 Matthew P. Braun
A1 Xiao Yu
A1 James L. Yergey
A1 Rominder Singh
YR 2003
UL http://dmd.aspetjournals.org/content/31/11/1437.abstract
AB Thrombin is a serine protease that plays a key role in the blood coagulation cascade. Compound I [2-[6-chloro-3-[(2,2-difluoro-2-pyridin-2-ylethyl)amino]-2-oxopyrazin-1(2H)-yl]-N-[(3-fluoropyridin-2-yl)methyl]acetamide] is a potent, selective, and orally bioavailable thrombin inhibitor that is being studied as a possible anticoagulant. Biotransformation studies in rats revealed that 84% of an i.v. dose of I was excreted in the form of two metabolites. Both metabolites were formed by metabolic activation of the pyrazinone ring in I and subsequent rearrangement leading to two novel dihydro-imidazole and imidazolidine derivatives. The structures of these metabolites and their mechanism of formation were elucidated by additional use of two 13C single labels in the pyrazinone ring of I in combination with mass spectrometry and NMR techniques. The metabolite structures described here illustrate the rich metabolic chemistry of the amino-pyrazinone heterocycle. The American Society for Pharmacology and Experimental Therapeutics