6CPW

Discovery of 3(S)-thiomethyl pyrrolidine ERK inhibitors for oncology.

Boga, S.B., Alhassan, A.B., Cooper, A.B., Doll, R., Shih, N.Y., Shipps, G., Deng, Y., Zhu, H., Nan, Y., Sun, R., Zhu, L., Desai, J., Patel, M., Muppalla, K., Gao, X., Wang, J., Yao, X., Kelly, J., Gudipati, S., Paliwal, S., Tsui, H.C., Wang, T., Sherborne, B., Xiao, L., Hruza, A., Buevich, A., Zhang, L.K., Hesk, D., Samatar, A.A., Carr, D., Long, B., Black, S., Dayananth, P., Windsor, W., Kirschmeier, P., Bishop, R.

(2018) Bioorg Med Chem Lett 28: 2029-2034

• PubMed: 29748051 Search on PubMed
• DOI: https://doi.org/10.1016/j.bmcl.2018.04.063
• Primary Citation of Related Structures:  
  6CPW


• PubMed Abstract: 
  

  Compound 5 (SCH772984) was identified as a potent inhibitor of ERK1/2 with excellent selectivity against a panel of kinases (0/231 kinases tested @ 100 nM) and good cell proliferation activity, but suffered from poor PK (rat AUC PK @10 mpk = 0 μM h; F% = 0) which precluded further development. In an effort to identify novel ERK inhibitors with improved PK properties with respect to 5, a systematic exploration of sterics and composition at the 3-position of the pyrrolidine led to the discovery of a novel 3(S)-thiomethyl pyrrolidine analog 28 with vastly improved PK (rat AUC PK @10 mpk = 26 μM h; F% = 70).

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Organizational Affiliation: 

Discovery Chemistry, Merck & Co., Inc., 2015 Galloping Hill Rd, Kenilworth, NJ 07033, United States. Electronic address: sobhana.babu.boga@merck.com.