Download MendeleyStructure-based design of 2,6,7-trisubstituted-7H-pyrrolo[2,3-d]pyrimidines as Aurora kinases inhibitors.
Le Brazidec, J.Y., Pasis, A., Tam, B., Boykin, C., Wang, D., Marcotte, D.J., Claassen, G., Chong, J.H., Chao, J., Fan, J., Nguyen, K., Silvian, L., Ling, L., Zhang, L., Choi, M., Teng, M., Pathan, N., Zhao, S., Li, T., Taveras, A.(2012) Bioorg Med Chem Lett 22: 4033-4037
- PubMed: 22607669
- DOI: https://doi.org/10.1016/j.bmcl.2012.04.085
- Primary Citation of Related Structures:
4DHF - PubMed Abstract:
This Letter reports the optimization of a pyrrolopyrimidine series as dual inhibitors of Aurora A/B kinases. This series derived from a pyrazolopyrimidine series previously reported as inhibitors of aurora kinases and CDKs. In an effort to improve the selectivity of this chemotype, we switched to the pyrrolopyrimidine core which allowed functionalization on C-2. In addition, the modeling rationale was based on superimposing the structures of Aurora-A kinase and CDK2 which revealed enough differences leading to a path for selectivity improvement. The synthesis of the new series of pyrrolopyrimidine analogs relied on the development of a different route for the two key intermediates 7 and 19 which led to analogs with both tunable activity against CDK1 and maintained cell potency.
Organizational Affiliation:
Biogen Idec, 5200 Research Place, San Diego, CA 92122, USA. [email protected]
