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BIOACTIVATION OF THE 3-AMINO-6-CHLOROPYRAZINONE RING IN A THROMBIN INHIBITOR LEADS TO NOVEL DIHYDRO-IMIDAZOLE AND IMIDAZOLIDINE DERIVATIVES: STRUCTURES AND MECHANISM USING ¹³C-LABELS, MASS SPECTROMETRY, AND NMR

Departments of Drug Metabolism (R.Su., C.C.L., C.R.G., X.Y., J.L.Y., R.Si.) and Medicinal Chemistry (S.M.P.), Merck Research Laboratories, West Point, Pennsylvania; and Department of Drug Metabolism, Merck Research Laboratories, Rahway, New Jersey (J.Z.H., M.P.B.)

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.