ORGN 502 |
| Vu Ma, Paul A. Tempest, Liping Pettus, Janan Jona, Charles Henley, Sekhar Surapaneni, Ella Magal, David Powers, Yan-yan Xie, Chris Mohr, Yax Sun, Steve Jordan, Bill Harte, Randall Hungate, Christopher Hulme, and Jim Meyer. Chemistry Research & Development, Amgen, One Amgen Center Drive, Thousand Oaks, CA 91320 |
| While stroke is the third leading cause of death and the leading cause of long-term disability in the U.S., treatment is limited only to thrombolytic agents, which target "ischemic" damage during a limited time frame. Although clot formation the major factor in ischemia, delayed cell death can spread for hours after restoration of blood flow (referfusion) and is mediated by a cascade of biochemical events, including apoptosis. Since JNK3 is a major target in the apoptotic pathway, we developed novel JNK3 inhibitors as potential therapeutic agents for stroke. We present a novel series of biochemically potent, blood brain barrier penetrating JNK3 small molecule inhibitors. Key issues for chemistry include 1) nM potency in the JNK3 enzymatic assay, 2) brain penetration and 3) aqueous solubility. Results from co-ligand-enzyme crystallization studies and subsequently developed SAR are reviewed. |
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Bioorganic, Molecular Recognition, Asymmetric Reactions and Syntheses
11:00 AM-1:00 PM, Wednesday, September 10, 2003 Javits Convention Center -- Hall 1B/1C, Poster
Division of Organic Chemistry |