| Autor: |
John Evenden, William L. Rumsey, David Aharony, Brian B. Masek, Gerard M. Koether, William Potts, Cyrus John Ohnmacht, Bruce Dembofsky, Bernstein Peter Robert, Jeffrey S. Albert |
| Rok vydání: |
2004 |
| Předmět: |
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| Zdroj: |
Tetrahedron. 60:4337-4347 |
| ISSN: |
0040-4020 |
| DOI: |
10.1016/j.tet.2004.03.054 |
| Popis: |
We have previously described a series of antagonists that showed high potency and selectivity for the NK1 receptor. However, these compounds also had the undesirable property of existing as a mixture of four interconverting rotational isomers. Through biological and structural analysis of the atropisomers, a binding model was developed and used to guide the design of compounds, which were rigidified by installation of a cyclizing linkage. These compounds existed as a mixture of two atropisomers. Further elaboration of the ring system reinforced the desired conformation and eliminated atropisomeric properties. We found that the region distal to the 8-membered ring system could be modified while retaining NK1 potency, and optimization led to further improvements in the in vivo activity. |
| Databáze: |
OpenAIRE |
| Externí odkaz: |
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