| Autor: |
Lampe JW; Sphinx Laboratories, Lilly Research Laboratories, Eli Lilly and Company, 20 T.W. Alexander Drive, Research Triangle Park, NC 27709, USA. lampe_john_w@lilly.com, Biggers CK, Defauw JM, Foglesong RJ, Hall SE, Heerding JM, Hollinshead SP, Hu H, Hughes PF, Jagdmann GE Jr, Johnson MG, Lai YS, Lowden CT, Lynch MP, Mendoza JS, Murphy MM, Wilson JW, Ballas LM, Carter K, Darges JW, Davis JE, Hubbard FR, Stamper ML |
| Jazyk: |
angličtina |
| Zdroj: |
Journal of medicinal chemistry [J Med Chem] 2002 Jun 06; Vol. 45 (12), pp. 2624-43. |
| DOI: |
10.1021/jm020018f |
| Abstrakt: |
A series of analogues of the protein kinase C (PKC) inhibitory natural product balanol which bear modified benzophenone subunits are described. The analogues were designed with the goal of uncovering structure-activity features that could be used in the development of PKC inhibitors with a reduced polar character compared to balanol itself. The results of these studies suggest that most of the benzophenone features found in the natural product are important for obtaining potent PKC inhibitory compounds. However, several modifications were found to lead to selective inhibitors of the related enzyme protein kinase A (PKA), and several specific modifications to the polar structural elements of the benzophenone were found to provide potent PKC inhibitors. In particular, it was found that replacement of the benzophenone carboxylate with bioisosteric equivalents could lead to potent analogues. Further, a tolerance for lipophilic substituents on the terminal benzophenone ring was uncovered. These results are discussed in light of recently available structural information for PKA. |
| Databáze: |
MEDLINE |
| Externí odkaz: |
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