| Literature DB >> 29748051 |
Sobhana Babu Boga1, Abdul-Basit Alhassan2, Alan B Cooper2, Ronald Doll2, Neng-Yang Shih2, Gerald Shipps3, Yongqi Deng3, Hugh Zhu2, Yang Nan3, Robert Sun2, Liang Zhu3, Jagdish Desai2, Mehul Patel3, Kiran Muppalla3, Xiaolei Gao2, James Wang2, Xin Yao2, Joseph Kelly2, Subrahmanyam Gudipati2, Sunil Paliwal2, Hon-Chung Tsui2, Tong Wang3, Bradley Sherborne2, Li Xiao2, Alan Hruza2, Alexei Buevich2, Li-Kang Zhang2, David Hesk2, Ahmed A Samatar2, Donna Carr2, Brian Long2, Stuart Black2, Priya Dayananth2, William Windsor2, Paul Kirschmeier2, Robert Bishop2.
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).Entities:
Keywords: ATP competitive; ERK inhibitor; Kinase selectivity; MAP kinases; Oncology
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Year: 2018 PMID： 29748051 DOI： 10.1016/j.bmcl.2018.04.063
Source DB: PubMed Journal: Bioorg Med Chem Lett ISSN： 0960-894X Impact factor: 2.823