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).
Original language | English |
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Pages (from-to) | 2029-2034 |
Number of pages | 6 |
Journal | Bioorganic and Medicinal Chemistry Letters |
Volume | 28 |
Issue number | 11 |
DOIs | |
State | Published - 15 Jun 2018 |
Keywords
- ATP competitive
- ERK inhibitor
- Kinase selectivity
- MAP kinases
- Oncology