Design and synthesis of factor Xa inhibitors and their prodrugs |
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Authors: | Song Yonghong Clizbe Lane Bhakta Chhaya Teng Willy Wong Paul Huang Brian Tran Katherine Sinha Uma Park Gary Reed Andrea Scarborough Robert M Zhu Bing Yan |
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Affiliation: | Department of Medicinal Chemistry, Millennium Pharmaceuticals, Inc., 256 East Grand Ave., South, San Francisco, CA 94080, USA. song@mpi.com |
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Abstract: | In addition to our previously reported fluoro acrylamides Xa inhibitors 2 and 3, a series of potent and novel cyclic diimide amidine compounds has been identified. In efforts to improve their oral bioavailability, replacement of the amidine group with methyl amidrazone gives compounds of moderate potency (14, IC(50)=0.028 microM). In the amidoxime prodrug approach, the amidoxime compounds show good oral bioavailability in rats and dogs. High plasma level of prodrug 26 and significant concentration of active drug 26a were obtained upon oral administration of prodrug 26 in rats. |
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