Identification of metabolites of the tryptase inhibitor CRA-9249: observation of a metabolite derived from an unexpected hydroxylation pathway |
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| Authors: | Yu Walter Dener Jeffrey M Dickman Daniel A Grothaus Paul Ling Yun Liu Liang Havel Chris Malesky Kimberly Mahajan Tania O'Brian Colin Shelton Emma J Sperandio David Tong Zhiwei Yee Robert Mordenti Joyce J |
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| Institution: | Department of Drug Metabolism and Pharmacokinetics, Celera Genomics, 180 Kimball Way, South San Francisco, CA 94080, USA. |
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| Abstract: | The metabolites of the tryptase inhibitor CRA-9249 were identified after exposure to liver microsomes. CRA-9249 was found to be degraded rapidly in liver microsomes from rabbit, dog, cynomolgus monkey, and human, and less rapidly in microsomes from rat. The key metabolites included cleavage of an aryl ether, in addition to an unexpected hydroxylation of the amide side chain adjacent to the amide nitrogen. The chemical structures of both metabolites were confirmed by synthesis and comparison to material isolated from the liver microsomes. Several suspected hydroxylated metabolites were also synthesized and analyzed as part of the structure identification process. |
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