Abstract
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.
Footnotes
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↵1 Abbreviations used are: MS, mass spectrometry; HPLC, high-performance liquid chromatography; DMSO, dimethyl sulfoxide; 1-D, one-dimensional; gHMQC, gradient heteronuclear multiple quantum coherence; gHMBC, gradient heteronuclear multibond coherence.
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Current address for M.V.S.-E.: Amgen Inc., One Amgen Center Drive (Mail Stop 5-2-A), Thousand Oaks, CA 91320
- Received July 7, 2003.
- Accepted August 19, 2003.
- The American Society for Pharmacology and Experimental Therapeutics
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