TY - JOUR 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 SP - 1437 LP - 1447 DO - 10.1124/dmd.31.11.1437 VL - 31 IS - 11 AU - Raju Subramanian AU - Charles C. Lin AU - Jonathan Z. Ho AU - Steven M. Pitzenberger AU - Maria V. Silva-Elipe AU - Christopher R. Gibson AU - Matthew P. Braun AU - Xiao Yu AU - James L. Yergey AU - Rominder Singh Y1 - 2003/11/01 UR - http://dmd.aspetjournals.org/content/31/11/1437.abstract N2 - 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 ER -