The design, synthesis and biological evaluation of a series of 4-aminopyrazolylpyrimidines as potent Trk kinase inhibitors is reported. High-throughput screening identified a promising hit in the 4-aminopyrazolylpyrimidine chemotype. Initial optimization of the series led to more potent Trk inhibitors. Further optimization using two strategies resulted in significant improvement of physical properties and led to the discovery of 10z (AZ-23), a potent, orally bioavailable Trk A/B inhibitor. The compound offers the potential to test the hypothesis that modulation of Trk activity will be of benefit in the treatment of cancer and other indications in vivo.

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In this paper we describe a series of 3-cyano-5-aryl-7-aminopyrazolo[1,5-a]pyrimidine hits identified by kinase-focused subset screening as starting points for the structure-based design of conformationally constrained 6-acetamido-indole inhibitors of CK2. The synthesis, SAR, and effects of this novel series on Akt signaling and cell proliferation in vitro are described.

Positive self-statements are widely believed to boost mood and self-esteem, yet their effectiveness has not been demonstrated. We examined the contrary prediction that positive self-statements can be ineffective or even harmful. A survey study confirmed that people often use positive self-statements and believe them to be effective. Two experiments showed that among participants with low self-esteem, those who repeated a positive self-statement ("I'm a lovable person") or who focused on how that statement was true felt worse than those who did not repeat the statement or who focused on how it was both true and not true. Among participants with high self-esteem, those who repeated the statement or focused on how it was true felt better than those who did not, but to a limited degree. Repeating positive self-statements may benefit certain people, but backfire for the very people who "need" them the most.